JP2728357B2 - Benzylidene derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel benzylidene derivative having an anti-inflammatory action.

[0002]

2. Description of the Related Art Conventionally, non-steroidal anti-inflammatory drugs, such as lysozyme chloride, have been effective in improving the initial symptoms and acute inflammation of rheumatism, but have progressed in bone destruction and the like. However, it is not effective for improvement of chronic rheumatic symptoms or treatment of osteoarthritis and the like, and has a strong effect of inducing gastric ulcer. Recently, such leukotrienes (LT), especially LTB ₄ is a metabolite of arachidonic acid metabolism pathway by 5-lipoxygenase have been shown to be an important mediator of the inflammatory response. In addition, it has been suggested that interleukin-1 (IL-1), which is a type of cytokine, is involved in inflammation, and in particular, is greatly involved in chronic rheumatism.
From the above background, compounds that inhibit the production of both LTB ₄ and IL-1 is considered to be promising as anti-inflammatory agents. Such compounds are expected to be effective not only for acute inflammation but also for chronic inflammation such as rheumatoid arthritis, and are therefore more useful than conventional nonsteroidal anti-inflammatory drugs.

[0003] Such anti-inflammatory agents are disclosed in JP-A-58-79.
944, JP-A-61-257967 and JP-A-62-297.
42977, JP-A-1-305028, JP-A-2-
4729, JP-A-2-256645, JP-A-2-2-2
Various compounds are disclosed in, for example, U.S. Pat. However, in order to obtain a compound which has few side effects such as gastric disorders and is effective for treating chronic inflammation, it is necessary to further effectively use prostaglandin E ₂ (PG
It is necessary to provide a compound having an action of suppressing the production of inflammatory mediators such as E ₂ ), LTB ₄ and IL-1.

[0004]

The present inventors have found that certain benzylidene derivatives inhibit the production of PGE ₂ very strongly and at the same time also inhibit the production of cytokines such as LTB ₄ and IL-1. The present invention has been completed.

That is, the present invention relates to a compound of the formula I:

Embedded image [In the formula, A is -CH ₂ - or -CH ₂ CH ₂ -; B is
Or represents a bond or _{-CH 2 -, - CHOH -,} - CO
-, -O-, or A and B together form -CH = C
H- may be formed; D is> N- or> C
H-; R ¹ and R ² are each independently hydrogen, lower alkyl or lower alkoxy; R ³ is hydrogen, lower alkyl, cycloalkyl, lower alkoxy; arylalkyloxy, heteroarylalkyloxy, lower alkylcarbonyl, Arylcarbonyl, substituted or unsubstituted carbamoyl, or a formula: — (CH ₂ ) _n —R ⁴ , wherein R ⁴ is hydrogen, hydroxy, substituted or unsubstituted amino, aryl, heteroaryl, hydroxycarbonyl or lower alkyloxy Carbonyl; n is 0-3
Represents a group represented by the following formula :).

Representative compounds of the present invention include, for example, compounds having a sulfur-containing heterocyclic moiety represented by the following formula.

Embedded image (In the formula, D represents> N− or> CH—.) A preferred compound of the formula I is a compound having a sulfur-containing heterocyclic moiety represented by the following formula.

[0007]

Embedded image As is apparent from the above formula, compound I can exist in any of the (E)-and (Z) -forms. Thus, unless otherwise specified, reference to compound I herein is intended to include both (E)-and (Z) -form stereoisomers.

Hereinafter, each term in this specification will be described. “Lower alkyl” means a C ₁ -C ₈ linear or branched alkyl group, and includes methyl, ethyl, n-
Propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, s-pentyl, t-pentyl, n-hexyl, neohexyl, i-hexyl, s-hexyl, t-hexyl, heptyl,
Octyl is exemplified. Among them, C ₁ -C ₄ linear or branched alkyl is preferred. Most preferred groups are methyl or ethyl. "Lower alkoxy" means a straight-chain or branched alkyloxy having 1 to 6 carbon atoms,
Methoxy, ethoxy, n-propoxy, i-propoxy, n
-Butoxy, i-butoxy, s-butoxy, t-butoxy, n-
Examples include pentyloxy, i-pentyloxy, neopentyloxy, s-pentyloxy, t-pentyloxy, n-hexyloxy, neohexyloxy, i-hexyloxy, s-hexyloxy, t-hexyloxy and the like. . Among them, C ₁ -C ₃ alkoxy is preferred. The most preferred group is methoxy. “Cycloalkyl” refers to C 3-7
, Which means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Among them, C ₃ -C ₅ cycloalkyl is preferred.

"Aryl" means unsubstituted or substituted phenyl or naphthyl, wherein the substituent is
Examples thereof include a halogen, a lower alkoxy, a lower alkyl and a nitro group, which may have one or more of these. For example,
Phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-nitrophenyl, 3,4-dichlorophenyl,
Examples include 3,4-dimethoxyphenyl, 3,4-dinitrophenyl, 1-naphthyl, 2-naphthyl, and the like. "Arylalkyloxy" is a group in which the lower alkoxy group is substituted with the aryl group.
Chlorobenzyloxy, 4-methoxybenzyloxy,
3,4-dichlorobenzyloxy, 3,4-dimethoxybenzyloxy, 4-nitrobenzyloxy, 2-phenylethyloxy, 2- (4-chlorophenyl) ethyloxy, 2- (4-methoxyphenyl) ethyloxy,
Examples thereof include 1-naphthylmethyloxy and 2-naphthylmethyloxy. Among them, benzyloxy is preferred. “Heteroaryl” is a group having 1-4 heteroatoms, and examples thereof include pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, and tetrazolyl. Preferred heterocycles for the present invention are pyridyl, thiazolyl, oxazolyl, imidazolyl. The most preferred group is pyridyl. "Halogen" refers to fluorine, chlorine, bromine,
Iodine. "Heteroarylalkyloxy" is a compound in which the above-mentioned heteroaryl group is substituted for the above-mentioned alkoxy group, and is 2-pyridylmethyloxy, 3-pyridylmethyloxy, 4-pyridylmethyloxy, 2-imidazolylmethyloxy, 4-imidazolylmethyl Oxy, 2-thiazolylmethyloxy, 4-thiazolylmethyloxy and the like are exemplified. "Lower alkylcarbonyl"
Means acetyl, propionyl, butyryl, valeroyl,
Hexayl, heptanoyl, octanoyl and the like are exemplified. "Arylcarbonyl" refers to benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl, 4-nitrobenzoyl, 3,4-dichlorobenzoyl, 3,4-dimethoxybenzoyl, 3,4-dinitrobenzoyl, 1-
Examples include naphthoyl and 2-naphthoyl. In the term `` substituted or unsubstituted carbamoyl '', the substituent is exemplified by lower alkyl, lower alkoxy, hydroxy, cycloalkyl, arylalkyl, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, cycloalkyloxy, arylalkyloxy,
These may substitute any one or more on the N atom. Among them, lower alkyl, lower alkoxy and hydroxy are preferable. For example, N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-hydroxycarbamoyl, N-
Methyl-N-hydroxycarbamoyl, N-methoxycarbamoyl, N-methoxy-N-methylcarbamoyl,
N-ethylcarbamoyl, N, N-diethylcarbamoyl, N-ethyl-N-hydroxycarbamoyl, N-propylcarbamoyl, N, N-dipropylcarbamoyl, N-propyl-N-hydroxycarbamoyl.

The "halogen" includes fluorine, chlorine, bromine and iodine. "Lower alkyloxycarbonyl" includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, te
rt-butoxycarbonyl and the like are exemplified. "Substituted amino" means mono- or di-substituted amino, and the substituent includes the lower alkyl and arylalkyl.

The compounds of the present invention exhibited excellent in vitro inhibitory effects on PGE ₂ , LTB ₄ and IL-1 production as compared with the control compound E5110 and indomethacin, as described in the experimental examples described later. In addition, it has an edema-suppressing effect in vivo and has a low effect of damaging the gastric mucosa, revealing the possibility of being an excellent nonsteroidal anti-inflammatory agent. The benzylidene derivative of the present invention is a novel compound and can be produced, for example, by the following method 1, but these do not limit the present invention in any way.

(1)

Embedded image Wherein A, B, D, R ¹ , R ² and R ³ are as defined above, and R ⁵ is hydrogen or a hydroxy protecting group.

Among the starting materials for the above reaction, the sulfur-containing heterocyclic compound 4 can be produced, for example, according to the following reaction formula.

Embedded image (Wherein R ³ is as defined above)

Reaction of 3-chlorosulfonyl chloride 1 'with amine 2 gives the sulfonamide intermediate 3 '. The reaction is carried out in the presence of a base (A), if necessary, in the presence of a solvent such as ether, chloroform, methylene chloride, dichloroethane, tetrahydrofuran, dimethoxyethane, diethoxyethane, benzene, toluene, xylene, ethyl acetate, methyl acetate, etc. This is performed using a solvent.
The amine (R ³ NH ₂ ) may be a hydrochloride. Examples of the base (A) used as needed include alkali metal salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, pyridine, 4-N, N-dimethylaminopyridine (DMAP) triethylamine, diisobutylethylamine, 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU), 1,4-diazabicyclo
Organic bases such as [2,2,2] octane (DABCO) are exemplified. When an alkali metal salt is used, it is preferable to add a phase transfer catalyst as needed. As the phase transfer catalyst, quaternary ammonium salts such as N-benzyltrimethylammonium salt and tetrabutylammonium salt are preferable. The reaction from the sulfonamide intermediate 3 ′ to the sulfur-containing heterocyclic compound 4 ′ can be performed in the same solvent as described above in the presence of the base (B), but an anhydrous solvent such as dimethyl sulfoxide or dimethylformamide is used. desirable. As the base (B), in addition to the above bases, sodium hydride and lithium hydride can be used.

As an alternative, it is possible to obtain the sulfur-containing heterocyclic compound 4 ′ at once without isolating the sulfonamide intermediate 3 ′ from the compound 1 ′. for that purpose,
For example, the reaction of compound 1 ′ with amine 2 is carried out in a suitable solvent,
Performed in the presence of 2 equivalents of base. Solvents and bases are selected from the above examples, with bases being sodium hydride,
It is particularly preferable to use dimethylformamide as the solvent.

[0016]

Embedded image Alternatively, the desired sulfur-containing heterocyclic compound 4 ′ can be obtained from commercially available γ-sultone 5 ′ (see Reference Example). That is, compound 5 ′ is reacted with an amine (R ³ NH ₂ ), and then a dehydrating agent is allowed to act. The reaction operation can be carried out without using a solvent, but may be carried out in the above-mentioned solvent if necessary. As the dehydrating reagent, a commonly used reagent such as phosphorus oxychloride, thionyl chloride, phosphorus pentachloride and phosphorus pentoxide can be used, but phosphorus oxychloride is particularly preferred.

R ^{5 in} compound 6 represents hydrogen or a hydroxy protecting group. Methoxymethyl as a hydroxy protecting group,
Examples include methoxyethoxymethyl, trimethylsilyl, tert-butyldimethylsilyl. R ⁵ is preferably a hydroxy protecting group, especially a methoxymethyl group. The aldol reaction of compound 6 with compound 4 obtained above is carried out in a suitable solvent in the presence of base (C). As the base (C), n-butyllithium, sec-butyllithium, tert-butyl
Organic lithium salts such as butyllithium, phenyllithium, lithium diisopropylamide, lithium diethylamide, and lithium hexamethyldisilazane; and alkali metal bases such as sodium hydride and potassium tert-butoxy. Particularly, lithium diisopropylamide, lithium hexamethyldisilazane and the like are preferable. Examples of the reaction solvent include ether solvents such as diethyl ether, tetrahydrofuran (THF), dimethoxyethane, and diethoxyethane, and hydrocarbon solvents such as n-hexane and cyclohexane. It is desirable to carry out the reaction in the presence of a reagent serving as a ligand of metal lithium, for example, tetramethylethylenediamine, hexamethylphosphoramide, or the like, if necessary. The reaction is carried out at a temperature of -80 ° C to + 50 ° C, but it is preferable to carry out the reaction at a lower temperature.

Aldol adduct 7 is prepared by reacting compound 7 in the presence of an acid with compound
Convert to 8 and 9 . Examples of the acid include organic acids such as trifluoroacetic acid, p-toluenesulfonic acid, and camphorsulfonic acid, and inorganic acids such as sulfuric acid and hydrochloric acid. Further, ordinary dehydrating reagents such as thionyl chloride, methanesulfonyl chloride, aluminum chloride, phosphorus oxychloride, and phosphorus pentachloride may be used. The reaction is desirably carried out under heating in an aromatic hydrocarbon such as benzene, toluene and xylene, a halogenated hydrocarbon such as chloroform, dichloromethane and dichloroethane, and an ether-based solvent such as tetrahydrofuran, dimethoxyethane and diethoxyethane.

(2)

Embedded image

The base (C) in the above formula has the same meaning as defined above. Y represents an N-protecting group, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-
Methoxybenzyl, 3,4-dimethoxybenzyl, 4-
And a nitrobenzyl group. The conditions for the aldol reaction are the same as in the above (1). Aldol adduct
Examples of the dehydration and deprotection reagents used for converting 7 into 10a and 10b include p-toluenesulfonic acid, trifluoroacetic acid aluminum chloride and titanium tetrachloride.
The conditions such as the reaction solvent and the temperature are the same as in the case (1).
The (E), (Z) mixture is deprotected and in formula I D> N
-, and R ³ is a hydrogen 10a, obtain 10b.

(3)

Embedded image

In this reaction, the compound of the present invention 10 obtained in the above formula (2) wherein D is> N- and R ³ is hydrogen in the formula I
Adding the desired substituent R ³ in, obtain various derivatives. R ³
When -X is an alkylating agent, the base (D) to be used is an alkali metal salt such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, lithium hydroxide or pyridine; Organic bases such as triethylamine and diisopropylethylamine are exemplified. The alkylation is preferably carried out using sodium hydroxide or potassium carbonate and sharing an appropriate quaternary ammonium salt as a phase transfer catalyst.

When R ³ X is an acylating agent, it is preferable to use an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine and diisopropylethylamine as the base (D). When R ³ X is a carbamoylating agent or an alkoxycarbonylating agent, it is preferable to use an organic lithium base such as n-butyllithium, lithium hexamethyldisilazane, lithium diisopropylamide as the base (D). However, the present invention is not limited to these, and organic bases such as pyridine, triethylamine and diisopropylethylamine or the above-mentioned alkali metal salts can also be used.

(4)

Embedded image

Compound8and9Is debenzylated to form a compound of formula I
Is> N-, R^ThreeIs a hydroxyl group11
a,11bGet. Debenzylation uses a deprotecting agent
Do. Deprotection in the presence of palladium carbon or platinum oxide catalyst
Hydrogenation or aluminum chloride, titanium tetrachloride, etc.
Using isocyanic acid, if necessary, anisole, 2,6-di-t
It can be carried out in the presence of ert-butylphenol, etc.
I can do it. Dichloromethane, chloropho
In addition to halogenated hydrocarbons such as lum and dichloroethane,
Also uses nitromethane, benzene, toluene, xylene, etc.
I can do it. The method according to the above (1), (2) and (3)
Is generally applicable to the preparation of Compound I of the present invention,
A specific example is shown in Example 1-35 described later.

Further, the compound I of the present invention has the following formula:

Embedded image Is reacted with a commonly used dehydrating reagent, for example, ethyl chlorocarbonate in the presence of triethylamine to give a ring-closed compound of the formula:

Embedded image Can be produced by a method comprising obtaining compound 8 of the formula (1). Examples of the dehydrating reagent include ethyl chloroformate, phosphorus oxychloride, thionyl chloride, and DCC (dicyclohexylcarbodiimide). This alternative method can also be generally applied to the production of compound I of the present invention by appropriately selecting starting materials and reaction conditions. Compound I of the present invention can be administered orally or parenterally as an anti-inflammatory agent. When administered orally, the compound of the present invention can be prepared in the usual preparations, for example, tablets, powders, granules,
It can be used as any dosage form of a solid preparation such as a capsule; a liquid preparation; an oily suspension; or a liquid preparation such as a syrup or an elixir. In the case of parenteral administration, the compound of the present invention can be used as an aqueous or oily suspension injection or an external preparation. In the preparation thereof, any of conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents and the like can be used, and other additives such as preservatives, stable It may contain an agent or the like. The dose of the compound of the present invention depends on the method of administration, the age of the patient,
Depending on body weight, condition and type of disease, it is usually orally 10 to 500 per day for adults.
mg, preferably 50 to 100 mg, or parenterally 1 to 250 mg, preferably 5 to 10 mg per day, which may be administered in 1 to 5 divided doses. Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited by these Examples. The abbreviations used in the examples have the following meanings. LDA: lithium diisopropylamide MOM: methoxymethyl p-TsOH: paratoluenesulfonic acid THF: tetrahydrofuran DMF: N, N-dimethylformamide HMPA: hexamethylphosphoramide LiHMDS: lithium hexamethyldisilazane DBU: 1,8-diazabicyclo [5 , 4,0] undec-7-ene DIBAL: diisobutylaluminum hydride

【Example】

Embedded image

Production Example 1 (R ³ = Et) N-ethyl-1,2-isothiazolidine-1,1-dioxy
Sid (4a) 3-chloropropylsulfonyl chloride 1 (6.1 gr,
34.5 mmol) in ethyl ether (25 ml)
(70% aqueous solution, 4.4 gr, 68.3 mmol) was added dropwise with stirring under ice-cooling, and after the dropwise addition was completed in about 15 minutes, the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and benzene 1 was added to the residue.
After adding 00 ml and distilling off the solvent under reduced pressure, 150 ml of ether was added to the residue and insoluble matters were filtered off. The ether was distilled off under reduced pressure to give crude N-ethyl-3-chloropropylsulfonamide intermediate. Compound 3a was obtained as colorless crystals having an mp of 30 to 32 ° C. Yield 6.96 gr (-100%). This intermediate 3a
Sodium hydride (60% oily, 1.52 gr, 38.0 mmol) was gradually added to a THF solution (50 ml) of (6.96 gr, 34.5 mmol) under ice-cooling and stirring, and the addition was completed in 15 minutes. did. Then, stirring was continued at room temperature for 30 minutes. Ether (50 ml) was added to the reaction mixture, and insolubles were filtered off. The solvent was distilled off under reduced pressure to obtain the target compound 4a as a pale yellow oil. Yield 4.93 gr (96%) IR (CHCl ₃ ) cm ⁻¹ : 3018,2976,2868,14
52, 1306, 1220, 1179, 1129, 1015. NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.4 Hz, C
_{H 3), 2.28-2.42 (2H,} m, CH 2), 3.10 (2H,
q, J = 7.4 Hz, CH ₂ ), 3.15 (2 H, t, J = 7.6 Hz,
_{CH 2), 3.22-3.29 (2H,} m, CH 2)

Production Example 2 (R ³ = Me) N-methyl-1,2-isothiazolidine-1,1-dioxy
Sid (4b) 3-chloropropylsulfonyl chloride 1 (16.8 g
r, 94.9 mmol), methylamine hydrochloride (13.5 gr, 20
0 mmol) and potassium carbonate (27.6 gr, 200 mmol) were sequentially added to ethyl acetate (500 ml), and N-benzyltrimethylammonium chloride (about 200 mg) was added to the mixture.
Was added and stirred at room temperature for 2 hours, and the reaction solution was dried over anhydrous sodium sulfate. The reaction solution was filtered through a small amount of silica gel and concentrated under reduced pressure to obtain a crude N-methyl-3-chloropropylsulfonamide intermediate 3b as a pale yellow oil. Yield 12gr (74%)

The intermediate 3b (11.79 gr, 68.69 mmol)
l) in benzene solution (300 ml) in DBU (10.79 ml,
After stirring at room temperature for 24 hours, the reaction solution was filtered through a small amount of silica gel, and the solvent was distilled off under reduced pressure to obtain the target compound 4b as a colorless solid having an mp of 36-40 ° C. Yield 7.0 gr (75%) IR (CHCl ₃ ) cm ⁻¹ : 3016,1451,1307,12
18,1187,1127. NMR (CDCl ₃ ) δ: 2.27-1.42 (2H, m, CH ₂ ),
_{2.69 (3H, s, CH 3} ), 3.11-3.20 (2H, m, CH
_{2), 3.22 (2H, t} , J = 6.8Hz, CH 2).

Production Example 3 (R ³ ＣＨCH ₂ CH (CH ₃ ) ₂ ) N-isobutyl-1,2-isothiazolidine-1,1-di
Oxide (4c) 3-chloropropylsulfonyl chloride 1 (7.08 g)
r, 40 mmol), isobutylamine (7.3 gr, 100 mmol)
l) and sodium hydrogen carbonate (3.36 gr, 40 mmol) were sequentially added to a mixture of ethyl acetate (200 ml) and water (20 ml), and N-benzyltrimethylammonium chloride (about 100 mg) was added thereto, and the mixture was added at room temperature for 3 hours. After stirring, the reaction solution was treated in the same manner as in Production Example 2 to give crude N-isobutyl-3-chloropropylsulfonamide intermediate 3c.
Obtained as colorless crystals at 68-69 ° C. Yield 8.19 gr (9
6%). DBU (3.3 ml, 22 mmol) was added to a benzene solution (60 ml) of this intermediate 3c (4.27 gr, 20 mmol), and the reaction solution was treated in the same manner as in Production Example 2 to give the target compound 4c.
Was obtained as a colorless oil. Yield 3.37 gr (95%). IR (CHCl ₃ ) cm ^-1 : 3016,2956,1465,13
04,1226,1131,1024 NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz, (C
_{H 3) 2), 1.75-1.96 (} 1H, m, CH), 2.27-2.
_{42 (2H, m, CH 2} ), 2.80 (2H, d, J = 7.4Hz, C
_{H 2), 3.10-3.19 (2H,} m, CH 2), 3.24 (2H,
t, J = 6.8 Hz, CH ₂ ).

Production Example 4 (R ³ = cyclopropyl) N-cyclopropyl-1,2-isothiazolidine-1,1
-Dioxide (4d) 3-chloropropylsulfonyl chloride 1 (7.08 g)
r, 40 mmol), cyclopropylamine (6.0 gr, 105 mm
ol) and sodium hydrogen carbonate (3.7 gr, 44 mmol) were treated in a mixture of ether (200 ml) and water (10 ml) in the same manner as in Preparation Example 3 to give crude N-cyclopropyl-3-chloropropylsulfone. Amide intermediate 3d to mp
Obtained as crystals at 48-49.5 ° C. Yield 8.0 gr (~ 1
(00%)

The above intermediate 3d (1.98 gr, 10 mmol) and DBU (1.65 ml, 11 mmol) were reacted in benzene (30 ml) in the same manner as in Preparation Example 2 to give the target compound 4d as a pale yellow oil. Obtained. Yield 1.40 gr (87%) IR (CHCl ₃ ) cm ⁻¹ : 3016,1309,1221,11
_{. 40,1026 NMR (CDCl 3) cm} -1: 0.60-0.85 (4H, m, cyclopropyl), 2.20-2.40 (2H, m, CH 2), 3.15
−3.25 (3H, m, CH ₂ + CH), 3.32 (2H, t, J =
6.6Hz, CH _2).

Production Example 5 (R ³ −—CH ₂ CH ₂ CH ₃ ) Nn-propyl-1,2-isothiazolidine-1,1-
Dioxide (4e) 3-chloropropyl chloride 1 (7.08 gr, 40 mmo
l), n-propylamine (5.90 gr, 100 mmol), potassium carbonate (5.52 gr, 40 mmol) and a small amount of N-benzyltrimethylammonium chloride (about 100 mg) in a mixture of ether (200 ml) and water (20 ml). After stirring at room temperature for 3 hours, the mixture was treated in the same manner as in Production Example 2 to give crude N-
The n-propyl-3-chloropropylsulfonamide intermediate 3e was obtained as crystals, mp 47.5-48 ° C. Yield 8.
0 gr (~ 100%). This intermediate 3e (2.0 gr, 10 mmol)
And DBU (1.65 ml, 11 mmol) in benzene (30 ml)
The reaction was carried out in the same manner as in Production Example 2 to obtain the desired compound 4e.
Was obtained as a pale yellow to colorless oil. Yield 1.41 gr (86
%) IR (CHCl ₃ ) cm ⁻¹ : 3018,2962,2868,13
04,1224,1130,1019 NMR (CDCl ₃ ) δ: 0.96 (3H, t, J = 7Hz, C
_{H 3), 1.52-1.72 (2H,} m, CH 2), 2.28-2.4
_{2 (2H, m, CH 2} ), 2.94-3.04 (2H, m, CH 2),
_{3.10-3.20 (2H, m, CH 2} ), 3.25 (2H, t, J =
6.7 Hz, CH ₂ )

Production Example 6 (R ³ ＯOCH ₃ ) N-methoxy-1,2-isothiazolidine-1,1-dioxide
Oxide (4f) 3-chloropropylsulfonyl chloride 1 (7.08 g)
r, 40 mmol), O-methylhydroxylamine hydrochloride
(3.67 gr, 40 mmol), potassium carbonate (5.80 gr, 42 m
mol) was reacted in the same manner as in Production Example 5 to give crude N-methoxy-3-chloropropylsulfonamide intermediate 3f
Was obtained as a colorless to pale yellow oil. Yield 7.02 gr (94
%). This intermediate 3f (6.25 gr, 33.3 mmol) was reacted with sodium hydride (60% oily, 1.47 gr, 36.7 mmol) in the same manner as in Production Example 1 to give the desired compound 4f.
Was obtained as a colorless oil. Yield 3.70 g (73%) IR (CHCl ₃ ) cm ⁻¹ : 3022,1355,1249,12
22,1165,1138,1035,1011. NMR (CDCl ₃ ) δ: 2.37-1.50 (2H, m, CH ₂ ),
_{3.20-3.14 (2H, m, CH 2} ), 3.50 (2H, t, J =
_{7.0Hz, CH 2), 3.81 (} 3H, s, OCH 3).

Production Example 7 (R ³ ＯOCH ₂ C ₆ H ₅ ) N-benzyloxy-1,2-isothiazolidine-1,1
-Dioxide (4 g) 3-chloropropylsulfonyl chloride 1 (30.28
gr, 0.17 mol), 27.3 g (0.17 mol) of O-benzylhydroxylamine hydrochloride, potassium carbonate (50 gr, 0.3
6 mol) and tetrabutylammonium sulfate (about 500 mg)
Was reacted at room temperature for 24 hours in a mixture of ether (1 l) and water (100 ml), and the reaction solution was extracted with ethyl acetate. The ethyl acetate extract was subjected to silica gel column chromatography, and 3 g of a crude N-benzyloxy-3-chloropropylsulfonamide intermediate was obtained from a fraction eluted from a mixed solution of ethyl acetate-n-hexane (1: 4) as a pale yellow oil. Obtained as a product. Yield 18.4gr (41%)

To a solution of 3 g (18.4 gr, 69.9 mmol) of the above intermediate in 150 ml of THF was added sodium hydride (60% oily, 2.94 gr, 73.4 mmol). After the reaction, the product was subjected to silica gel column chromatography. From the fraction eluted from a mixed solution of ethyl acetate-n-hexane (1: 5), 4 g of the desired compound was obtained as mp52-54.
As colorless crystals. Yield 10.75 gr (68%) IR (CHCl ₃ ) cm ⁻¹ : 3022,2956,1453,13
54,1165,1140,1081,1000 NMR (CDCl ₃ ) δ: 2.30-2.48 (2H, m, CH ₂ ),
_{3.04-3.14 (2H, m, CH 2} ), 3.45 (2H, t, J =
6.9 Hz, CH ₂ ), 5.00 (2 H, s, OCH ₂ ), 7.30 −
_{7.45 (5H, m, C 6} H 5).

Production Example 8 (R ³ = 4-methoxybenzyl) N- (4-methoxybenzyl-1,2-isothiazolidine )
-1,1-dioxide (4h) 3-chloropropylsulfonyl chloride 1 (17.7 g
r, 0.1 mol), p-methoxybenzylamine (15.0 gr,
0.11 mol) and sodium hydrogen carbonate (8.4 gr, 0.1 mol
l) was reacted in a mixture of ethyl acetate (400 ml) and water (40 ml) in the same manner as in Preparation Example 3 to give crude N- (4
-Methoxybenzyl) -3-chloropropylsulfonamide intermediate 3h was obtained as colorless crystals having a mp of 78 ° C to 80 ° C. Yield 19.1 gr (69%) The above intermediate 3h (11.11 gr, 40 mmol) and DBU (6.1.
6 ml, 40 mmol) in benzene (150 ml),
The target compound 4h was treated in the same manner as in Production Example 2 to obtain
Obtained as crystals at 51 ° C. Yield 8.89 gr (92%) IR (CHCl ₃ ) cm ⁻¹ : 3016,1612,1511,13
04,1245,1136,1034 NMR (CDCl ₃ ) cm ^-1 : 2.20-2.38 (2H, m, C
_{H 2), 3.09 (2H,} t, J = 6.8Hz, CH 2), 3.14-
3.24 (2H, m, CH ₂ ), 3.81 (3H, s, OCH ₃ ), 4.
_{12 (2H, s, CH 2} ), 6.84-6.94 (2H, m, CH 2),
7.22-7.32 (4H, m, 4 × aromatic-H)

Production Example 9 (R ³ = 3,4-dimethoxybenzyl) N- (3,4-dimethoxybenzyl) -1,2-isothiazo
Lysine-1,1-dioxide (4i) 3-chloropropylsulfonyl chloride 1 (8.85 g)
r, 50 mmol), 3,4-dimethoxybenzylamine (9.0
ml, 60 mmol) and potassium carbonate (4.14 gr, 30 mmol) were reacted in the same manner as in Preparation Example 2 to give crude N- (3,4-
Dimethoxybenzyl) -3-chloropropylsulfonamide intermediate 3i was obtained. Yield 14.5 gr (94%). The target compound 4i was obtained from the intermediate 3i according to the method of Production Example 1.
Yield 69% IR (CHCl ₃ ) cm ⁻¹ : 3018,1516,1307,12
62,1225,1155,1138,1027 NMR (CDCl ₃ ) δ: 2.22-2.38 (2H, m, CH ₂ ),
3.11 (2H, t, J = 6.7Hz, CH 2), 3.16-3.2
_{5 (2H, m, CH 2} ), 3.88 (3H, s, OCH 3), 3.89
_{(3H, s, OCH 3)} , 4.12 (2H, s, CH 2), 6.79-
6.91 (3H, m, 3 × aromatic-H)

Production Example 10 (R ³ ＣC ₆ H ₅ ) N-phenyl-1,2-isothiazolidine-1,1-dioxide
Oxide (4j) 3-chloropropylsulfonyl chloride 1 (1.456)
gr, 8.23 mmol) was added dropwise to a pyridine solution (5 ml) of aniline (0.5 ml, 8.23 mmol) at −20 ° C. to −30 ° C. under cooling, and after about 5 minutes, the reaction was completed. 45 more at room temperature
Stirred for minutes. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and N-phenyl-
3-Chloropropylsulfonamide intermediate 3j was obtained as a yellow oil. Yield 1.683 g (88%). From this intermediate 3j, the target compound 4j was obtained as a pale yellow solid according to the method of Production Example 1. Yield 57% IR (CHCl ₃ ) cm ^-1 : 3020,1598,1495,13
15,1139. NMR (CDCl ₃ ) δ: 2.46-2.60 (2H, m, CH ₂ ),
_{3.34-3.42 (2H, m, CH 2} ), 3.78 (2H, t, J =
_{6.6Hz, CH 2), 7.10-7.40 (} 5H, m, C
₆ H _5).

Production Example 11 (R ³ = 4-chlorophenyl) N- (4-chlorophenyl) -1,2-isothiazolidine
-1,1-dioxide (4k) N- (4-chlorophenyl) -3-chloropropylsulfone was reacted with 3-chloropropylsulfonyl chloride and 4-chloroaniline in pyridine in the same manner as in Production Example 10. The amide intermediate 3k was obtained. Yield 93%.
Next, this intermediate 3k was converted into D by the same method as in Production Example 2.
After treatment with BU, the target compound 4k was obtained as mp 110.5-111.
Obtained as colorless crystals at 5 ° C. Yield 68% IR (KBr) cm ^-1 : 3010,2960,1595,149
3,1300,1267,1131. NMR (CDCl ₃ ) δ: 2.47-2.61 (2H, m, CH ₂ ),
_{3.35-3.43 (2H, m, CH 2} ), 3.76 (2H, t, J =
6.4 Hz, CH ₂ ), 7.16-7.36 (4 H, m, 4 × aromat
ic-H)

Production Example 12 (R ³ = 2-pyridyl) N- (2-pyridyl) -1,2-isothiazolidine-1,1
-Dioxide (4 l) 3-chloropropylsulfonyl chloride and 2-aminopyridine were reacted in the same manner as in Production Example 10 to give N
31 of the-(2-pyridyl) -3-chloropropylsulfonamide intermediate was obtained as a pale yellow solid. Yield 54%. Then, sodium hydride (60% oil, 60% oil,
After stirring at 85 ° C. for 30 minutes, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to give ethyl acetate-n-hexane.
(1: 1) 4 l of the desired compound was obtained as a yellow solid from the fraction eluted with the mixed solution. Yield 1.806 g (100%) IR (CHCl ₃ ) cm ⁻¹ : 3022,1592,1473,14
34,1139. NMR (CDCl ₃ ) δ: 2.47-2.60 (2H, m, CH ₂ ),
3.43 (2H, t, J = 7.5Hz, CH 2), 4.05 (2H, t,
J = 6.6 Hz, CH ₂ ), 6.88-7.02 (1 H, m, CH),
7.26-7.35 (1H, m, CH), 7.58-7.70 (1
H, m, CH), 8.33 (1H, d, J = 4.4Hz, CH)

Production Example 13 (R ³ = 3-pyridyl) N- (3-pyridyl) -1,2-isothiazolidine-1,1
- dioxide (4m) 3-chloropropyl sulfonyl in the same manner as in Preparation Example 10 chloride 1 (7.28g, 41.1mmol) and 3-aminopyridine (4.6gr, 49.3mmol) in pyridine (15ml)
To give a crude 3M intermediate of N- (3-pyridyl) -3-chloropropylsulfonamide as a colorless solid. Yield 4.50 g (46%)

3m of this intermediate (232mg, 0.988mmol)
In sodium hydride (60% oil, 4 ml) in DMF (5 ml).
(3.5 mg, 1.09 mmol) in the same manner as in Production Example 12 to obtain the target compound (4 m) as a colorless solid. Yield 19
0 mg (97%) IR (CHCl ₃ ) cm ⁻¹ : 3022,2960,1590,14
84, 1428, 1319, 1142. NMR (CDCl ₃ ) δ: 2.53-2.67 (2H, m, CH ₂ ),
_{3.38-3.45 (2H, m, CH 2} ), 3.83 (2H, t, J =
_{6.6Hz, CH 2), 7.28-7.36 (} 1H, m, CH), 7.
73-7.79 (1H, m, CH), 8.41 (1H, d, J = 4.
6 Hz, CH), 8.46 (1 H, d, J = 2.4 Hz, CH)

Production Example 14 (R ³ = 4-pyridyl) N- (4-pyridyl) -1,2-isothiazolidine-1,1
-Dioxide (4n) 3-chloropropylsulfonyl chloride 1 (3 ml, 2
4.7 mmol) and 4-aminopyridine (2.32 g, 24.7 mmol)
Sodium hydride (60% oily, 2.17 g, 54.3 mmol) was gradually added to a DMF solution (25 ml) of the above l) under ice-cooling and stirring over about 5 minutes. Then, stirring was continued at 50 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the target compound 4n was obtained as a yellow solid from a fraction eluted with a methylene chloride-methanol (10: 1) mixed solution. Yield 1.294 gr (27%) IR (CHCl ₃ ) cm ⁻¹ : 3024,2956,1597,15
04,1320,1143 NMR (CDCl ₃ ) δ: 2.53-2.67 (2H, m, CH ₂ ),
3.43 (2H, t, J = 7.6 Hz, CH ₂ ), 3.81 (2H, t,
J = 6.6 Hz, CH ₂ ), 7.08 (2 H, d, J = 5.4 Hz, C
H), 8.49 (2H, d, J = 5.4Hz, CH)

[0045]

Embedded image Example 1 (R^Three= Et)(E) -2-ethyl-5- (3,5-di-tert-butyl-4
-Hydroxy) benzylidene-1,2-isothiazolidine
-1,1-dioxide (8a) and its (Z) -isomer (9
a) During ice melting, diisopropylamine (15.5 ml, 110.6 mm
ol) in n-hexane solution of n-butyllithium (1.6 M, 6
9.5 ml, 111 mmol) are added dropwise over 20 minutes with stirring.
Stir for an additional 15 minutes after the end of the bottom. Bring the reaction to -78 ° C
After cooling, 100 ml of THF was added and N-ethyl-1,2-
Isothiazolidine-1,1-dioxide 4a (15gr, 1
0.5 mmol) 3,5-di-tert-butyl-4-methoxy
Cymethoxybenzaldehyde 6a (25 g, 90.5 mmol)
And a solution of HMPA (30 ml) in THF (70 ml) with stirring
After dropping in 15 minutes, continue stirring at the same temperature for 30 minutes
did. After the temperature of the reaction solution was raised to room temperature, cold 2N-HCl was added.
(100 ml) and extracted twice with ethyl acetate (250 ml).
And remove the ethyl acetate layer with dilute aqueous sodium bicarbonate solution (3
00 ml) and then with saturated saline (300 ml), then dried
Dried over sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is
After performing ricagel column chromatography,
The product was purified by elution with ethyl acetate (4: 1 to 1: 1).
The dol adduct 7a was obtained as a colorless solid. Yield 21.3gr
(55%). The toll of this adduct 7a (8.5 gr, 19.9 mmol)
P-Toluenesulfonic acid hydrate in ene solution (150 ml)
(2.49 gr, 13 mmol) was added and the mixture was heated under reflux for 30 minutes.
Thereafter, the reaction mixture was diluted with a dilute aqueous sodium hydrogen carbonate solution (150 ml).
And extracted twice with ethyl acetate (150 ml).
Was washed with water (150 ml) and then with saturated saline (150 ml).
Then, it was dried over anhydrous sodium sulfate. Solvent is removed under reduced pressure
The residue is subjected to silica gel column chromatography.
And the fraction eluted with n-hexane-ethyl acetate (3: 1)
The desired compounds 9a and 8a were sequentially obtained. Yield 8a: 2.59 g
r (36%); 9a: 376 mg (7%).

8a: mp 135-137 ° C. IR (KBr) cm ⁻¹ : 3610,3440,2970,288
0,1645,1597,1430,1290,1173,1
151,1139. NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.2Hz, C
_{H 3), 1.45 (18H,} s, 2 × Bu t), 3.07-3.19
_{(4H, m, CH 2)} , 3.28 (2H, q, J = 7.2Hz, CH 2),
5.50 (1H, s, OH), 7.24-7.26 (3H, m, 2 × a
. romatic-H, CH) Elemental analysis _{(C 20 H 31 NO 3 S} ) Calcd: C, 65.71; H, 8.55 ; N, 3.83; S, 8.
77 Found: C, 65.65; H, 8.43; N, 3.85; S, 8.
78

9a: mp 137-138 ° C. IR (KBr) cm ⁻¹ : 3560, 2975, 1637, 160
0,1431,1289,1275,1168,1150,1
111 NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.2 Hz, C
_{H 3), 1.45 (18H,} s, 2 × Bu t), 3.00 (2H, dt,
J = 2.0, 6.0 Hz ,, CH ₂ ), 3.15 (2 H, q, J = 7.
_{2Hz, CH 2), 3.25 (} 2H, t, J = 6.0Hz, CH 2),
5.47 (1H, s, OH), 6.73 (1H, t, J = 2.0Hz,
. CH), 7.52 (2H, s, 2 × aromatic-H) Elemental analysis _{(C 20 H 31 NO 3 S} ) Calcd: C, 65.71; H, 8.55 ; N, 3.83 ; S, 8.
77 Found: C, 65.68; H, 8.43; N, 3.61; S, 8.
66

Example 2 (R ³ ＣＨCH ₃ ) (E) -2-methyl-5- (3,5-di-tert-butyl-4
-Hydroxy) benzylidene-1,2-isothiazolidine
-1,1-Dioside (8b) and its (Z) -isomer (9b) According to the same method as in Example 1, compound 6a (3.34 gr,
12 mmol) and N-methyl-1,2-isothiazolidine-
Aldol reaction with 1,1-dioxide 4b (1.35 gr, 10 mmol) gave adduct 7b. Yield 1.65gr (40
%). To a toluene solution (30 ml) of this adduct 7b (1.60 gr, 3.87 mmol) was added p-toluenesulfonic acid hydrate (160 ml).
mg) and heated to reflux for 30 minutes. The reaction product was subjected to silica gel column chromatography, and the target compounds 8b and 9b were obtained from fractions eluted from a mixed solution of n-hexane-ethyl acetate (3: 7). Yield 8b: 580 mg (43%);
9b: 200 mg (15%)

8b: mp 168-170 ° C IR (CHCl ₃ ) cm ^-1 : 3620,2956,1435,12
_{. 92,1218,1149 NMR (CDCl 3) δ} : 1.45 (18H, s, 2 × Bu t), 2.
76 (3H, s, NCH ₃ ), 3.07-3.18 (2H, m, C
_{H 2), 3.20-3.32 (2H,} m, CH 2), 5.51 (1H,
s, OH), 7.23-7.29 (3H, m, 2 × aromatic-H,
CH). Elemental analysis (C ₁₉ H ₂₉ NO ₃ S) Calculated: C, 64.92; H, 8.32; N, 3.98; S, 9.
12 found: C, 64.62; H, 8.31; N, 3.95; S, 9.
149b: mp 152-163 ° C IR (CHCl ₃ ) cm ^-1 : 3622,2956,1433,12
_{93,1241,1160,1010 NMR (CDCl 3) δ:} 1.45 (18H, s, 2 × Bu t), 2.
_{75 (3H, s, NCH 3} ), 2.95-3.05 (2H, m, C
_{H 2), 3.16-3.26 (2H,} m, CH 2), 5.49 (1H,
(s, OH). 6.75 (1H, t, J = 2.2Hz, CH), 7.58
(2H, s, 2 × aromatic-H) Elemental analysis (C ₁₉ H ₂₉ NO ₃ S) Calculated: C, 64.92; H, 8.32; N, 3.98; S, 9.
12 found: C, 64.61; H, 8.29; N, 3.95; S, 9.
07

Example 3 (R ³ ＣＨCH ₂ CH (CH ₃ ) ₂ ) (E) -2-isobutyl-5- (3,5-di-tert-butyl
-4-Hydroxy) benzylidene-1,2-isothiazoly
Gin-1,1-dioxide (8c) Compound 6a (2.78 gr, 1c) was prepared in the same manner as in Example 1.
0 mmol) and N-isobutyl-1,2-isothiazolidine-1,1-dioxide 4c (1.95 gr, 11 mmol) to give the adduct 6c. Yield 3.67 gr (8
1%) This adduct 7c (3.60 gr, 7.9 mmol) was prepared in Example 1.
P-Toluenesulfonic acid hydrate (36
0 mg) and toluene (50 ml). The product was subjected to silica gel column chromatography, and the desired compound 8c was obtained from the fraction eluted with a mixed solution of n-hexane-ethyl acetate (1: 3). Yield 1.30 gr (42%), mp 167-1
70 ° C IR (CHCl ₃ ) cm ^-1 : 3620,2956,1646,14
35, 1289, 1240, 1148, 1081 NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.4 Hz, (C
_{H 3) 2), 1.45 (} 18H, s, 2 × Bu t), 1.81-2.0
2 (1H, m, CH), 2.87 (2H, d, J = 7.4Hz, C
_{H 2), 3.06-3.18 (2H,} m, CH 2), 3.22-3.3
_{3 (2H, m, CH 2} ), 5.50 (1H, s, OH), 7.23-7.
27 (3H, m, 2 × aromatic-H, CH) Elemental analysis _{(C 22 H 35 NO 3 S} ) Calcd: C, 67.14; H, 8.96 ; N, 3.56; S, 8 .
15 found: C, 66.85; H, 8.99; N, 3.58; S, 8.
11

Example 4 (R ³ = cyclopropyl) (E) -2-cyclopropyl-5- (3,5-di-tert-butyl
(Tyl-4-hydroxy) benzylidene-1,2-isothia
Zolidine-1,1-dioxide (8d) According to the same method as in Example 1, compound 6a (2.67 gr,
9.6 mmol) and N-cyclopropyl-1,2-isothiazolidine-1,1-dioxide 4d (1.29 gr, 8.0 mmol)
Aldol reaction with 1) gave adduct 7d. Yield 3.09 gr (88%). This adduct 7d (3.0 g, 7 mmol) was treated with p-toluenesulfonic acid hydrate (30 ml) in toluene (50 ml).
0 mg). The reaction product was purified in the same manner as in Example 3 to obtain target compound 8d. Yield 1.03gr
(40%). mp 202-204 ° C IR (CHCl ₃ ) cm ^-1 : 3620,2956,1434,12
97,1237,1145 NMR (CDCl ₃ ) δ: 0.68-0.90 (4H, m, 2 × C
_{H 2), 1.44 (18H,} s, 2 × Bu t), 2.28-2.40
(1H, m, CH), 3.08 (2H, dt, J = 2.6,6.7Hz,
CH ₂ ), 3.36 (2H, t, J = 6.7 Hz, CH ₂ ), 5.51
(1H, s, OH), 7.20-7.25 (3H, m, 2 × aromatic
-H, CH), elemental analysis (C ₂₁ H ₃₁ NO ₃ S) Calculated: C, 66.81; H, 8.28; N, 3.71; S, 8.
49 found: C, 66.67; H, 8.29; N, 3.71; S, 8.
38

Example 5 (R ³ ＣＨCH ₂ CH ₂ CH ₃ ) (E) -2-n-propyl-5- (3,5-di-tert-butyl)
(4-hydroxy) benzylidene-1,2-isothiazo
Lysine-1,1-dioxide (8e) and its (Z) -isomer
(9e) In the same manner as in Example 1, compound 6a (2.78 gr,
10 mmol) and N-n-propyl-1,2-isothiazolidine-1,1-dioxide 4e (1.35 gr, 8.27 mmol)
The adduct 7e was obtained by the aldol reaction with Yield 1.5
gr (41%). This adduct 7e was treated with p-toluenesulfonic acid hydrate (400 mg) in the same manner as in Example 1. The reaction product was subjected to silica gel column chromatography, and the target compounds 8e and 9e were obtained from fractions eluted with a mixed solution of n-hexane-ethyl acetate (1: 4). Yield 8e:
810 mg (26%); 9e: 120 mg (3.8%)

8e: mp 181-183 ° C. IR (CHCl ₃ ) cm ⁻¹ : 3616,2954,1435,12
89,1146 NMR (CDCl ₃ ) cm ⁻¹ : 0.98 (3H, t, J = 7.4 Hz,
_{CH 3), 1.45 (18H,} s, 2 × Bu t), 1.57-1.7
8 (2H, m, CH ₂ ), 2.98-3.20 (4H, m, 2 × C
_{H 2), 3.22-3.34 (2H,} m, CH 2), 5.50 (1H,
s, OH), 7.23-7.27 (3H, m, 2 × aromatic-H,
CH) Elemental analysis (C ₂₁ H ₃₃ NO ₃ S) Calculated: C, 66.45; H, 8.76; N, 3.69; S, 8.
45 found: C, 66.25; H, 8.74; N, 3.70; S, 8.
339 e: mp 123-124.5 ° C IR (CHCl ₃ ) cm ^-1 : 3622,2958,1433,12
89,1164 NMR (CDCl ₃ ) δ: 0.96 (3H, t, J = 7.4 Hz, C
_{H 3), 1.45 (18H,} s, 2 × Bu t), 1.55-1.72
_{(2H, m, CH 2)} , 2.95-3.08 (4H, m, 2 × CH 2),
_{3.20-3.29 (2H, m, CH 2} ), 5.47 (1H, s, O
H), 6.74 (1H, t, J = 2.1 Hz, CH), 7.57 (2
H, s, 2 × aromatic-H).

[0054]Example 6 (R^Three= OCH_Three)(E) -2-methoxy-5- (3,5-di-tert-butyl-
4-hydroxy) benzylidene-1,2-isothiazolidy
1,1-dioxide (8f) and its (Z) -isomer (9
f) According to a method similar to that of Example 1, compound 6a (5.56 gr,
20 mmol) and N-methoxy-1,2-isothiazolidine
Alkylation with -1,1-dioxide 4f (3.32 gr, 22 mmol)
The adduct 7f was obtained by the Dole reaction. Yield 6.89gr
(80%). Implement this adduct 7f (6.89gr, 16mmol)
According to the same method as in Example 1, p-toluene was added in toluene (100 ml).
Treated with ruenesulfonic acid hydrate (1 gr). Reaction product
Was subjected to silica gel column chromatography, and n-
From the fraction eluted from a mixed solution of xan-ethyl acetate (6: 1)
The target compounds 8f and 9f were obtained. Yield 8f: 2.40 gr (41
%); 9f: 500 mg (8.5%) 8f: mp 166-168 ° C IR (CHCl_Three)cm^-1: 3616,2952,1639,14
36, 1340, 1240, 1158, 1002. NMR (CDCl_Three) δ: 1.45 (18H, s, 2 × Bu^t), 3.
11 (2H, dt, J = 2.8, 7.0Hz, CH_Two), 3.66 (2
H, t, J = 7Hz, CH_Two), 3.81 (3H, s, OCH_Three), 5.
55 (1H, s, OH), 7.25-7.35 (3H, m, 3 × arom
atic-H, CH) Elemental analysis value (C₁₉H₂₉NO_FourS) Calculated: C, 62.10; H, 7.95; N, 3.81; S, 8.
72 found: C, 61.90; H, 7.88; N, 3.91; S, 8.
67 9f; mp 173-176 ° C IR (CHCl_Three)cm^-1: 3616,2950,1431,13
41,1240,1155,1010 NMR (CDCl_Three) δ: 1.45 (18H, s, 2 × Bu^t), 3.
12 (2H, dt, J = 2.2,6.8Hz, CH_Two), 3.61 (2
H, t, J = 6.8Hz, CH_Two), 3.61 (3H, s, OCH_Three),
5.49 (1H, s, OH), 7.01 (1H, t, J = 2.2Hz,
CH), 7.49 (2H, s, 2 × aromatic-H) Elemental analysis (C₁₉H₂₉NO_FourS × 0.4H_TwoO) Calculated: C, 60.90; H, 8.02; N, 3.74; S, 8.
56 Found: C, 61.08; H, 7.76; N, 3.75; S, 8.
61

Example 7 (R ³ ＯOCH ₂ C ₆ H ₅ ) (E) -2-benzyloxy-5- (3,5-di-tert-butyl
(Tyl-4-hydroxy) benzylidene-1,2-isothia
Zolidine-1,1-dioxide (8 g) Compound 6a (15 gr, 54 g) was prepared in the same manner as in Example 1.
mmol) and 4 g (10.23 gr, 45 mmol) of N-benzyloxy-1,2-isothiazolidine-1,1-dioxide to give 7 g of the adduct. Yield 15.51
gr (68%). 7 g (10.21 gr, 20.2 mmol) of this adduct
Was converted to p-toluenesulfonic acid in the same manner as in Example 1.
(1 gr) and toluene (150 ml). The reaction product was filtered through a small amount of silica gel, and the filtrate was concentrated under reduced pressure to obtain 8 g of the desired compound. Yield 5.32gr (59%) mp
134-135 ° C IR (CHCl ₃ ) cm ^-1 : 3620,2956,1639,14
36,1339,1241,1159 NMR (CDCl ₃ ) δ: 1.44 (18H, s, 2 × Bu ^t ), 3.
09 (2H, dt, J = 2.6, 6.8 Hz, CH ₂ ), 3.58 (2
H, t, J = 6.8Hz, CH ₂ ), 5.02 (2H, s, OCH ₂ ),
5.53 (1H, s, OH), 7.25-7.45 (8H, m, 7 × a
romatic-H, CH). Elemental analysis (C ₂₅ H ₃₃ NO ₄ S) Calculated: C, 67.69; H, 7.50; N, 3.16; S, 7.
23 found: C, 67.52; H, 7.59; N, 3.18; S, 7.
16

Example 8 (R ³ = 4-methoxybenzyl) (E) -2- (4-methoxybenzyl) -5- (3,5-di-
(tert-butyl) benzylidene-1,2-isothiazolidine
-1,1-dioxide (8h) and its (Z) -isomer (9h) Compound 6a (9 gr, 32 mmol) was prepared in the same manner as in Example 1.
1) and N- (4-methoxybenzyl) -1,2-isothiazolidine-1,1-dioxide 4h (7.24 gr, 30 mmol) gave an adduct 7h by an aldol reaction. Yield 13.1
6gr (84%). This adduct 6h (12.6 gr, 24.2 mmol)
Was treated with p-toluenesulfonic acid hydrate (1.3 gr) in toluene (150 ml) in the same manner as in Example 1 to obtain a mixture of the target compounds 8h and 9h. Yield 8.83 gr.

Example 9 (R ³ = 3,4-dimethoxybenzyl) (E) -2- (3,4-dimethoxybenzyl) -5- (3,5
-Di-tert-butyl-4-hydroxy) benzylidene-
1,2-isothiazolidine-1,1-dioxide (8i) and
The (Z) -isomer (9i) Compound 6a (5.6 gr, 20 m
mol) and N- (3,4-dimethoxy) benzyl-1,2-isothiazolidine-1,1-dioxide 4i (5.85 g, 2
(1.6 mmol) to give the adduct 7i. Yield 9.25 g (78%). This adduct 7i (4gr, 7.3
In the same manner as in Example 1, dehydration and deprotection were carried out to obtain a mixture of the target compounds 8i and 9i. Yield 2.5 gr.

[0058]Example 10 (R^Three= C₆H_Five)(E) -2-phenyl-5- (3,5-di-tert-butyl-
4-hydroxy) benzylidene-1,2-isothiazolidy
1,1-dioxide (8j) and its (Z) -isomer (9
j) Compound 6a (2.47 gr, 8.88) was prepared in the same manner as in Example 1.
mmol) and N-phenyl-1,2-isothiazolidine-
With 1,1-dioxide 4j (2.19 gr, 11.10 mmol)
An aldol reaction was carried out to obtain an adduct 7j. 3.18 yield
4gr (75%). This additional product 7j (3.184 g, 6.69 mmo
l) in toluene (100 ml), p-toluenesulfonic acid aqueous solution
This was treated with the hydrate (750 mg) to obtain the desired compounds 8j and 9j.
Yield 8j: 667 mg (24%); 9j: 110 mg (4%)

8j: mp 195-196 ° C IR (KBr) cm ^-1 : 3560,3520,2960,163
6,1593,1492,1430,1295,1268,1
105,1092 IR (CDCl ₃ ) δ: 1.47 (18H, s, 2 × Bu ^t ), 3.3
1 (2H, dt, J = 2.6,6.6Hz, CH ₂ ), 3.80 (2H, dt
t, J = 6.6 Hz, CH ₂ ), 5.54 (1 H, s, OH), 7.17
−7.26 (2H, m, aromatic-H, CH), 7.29 (2H,
s, 2 × aromatic-H), 7.38-7.42 (4H, m, 4 × ar
. omatic-H) Elemental analysis _{(C 24 H 31 NO 3 S} × 0.1H 2 O) Calcd: C, 69.39; H, 7.61 ; N, 3.37; S, 7.
72 found: C, 69.27; H, 7.60; N, 3.39; S, 7.
609j: mp 172-174 ° C IR (KBr) cm ^-1 : 3540,2960,1629,159
8,1503,1435,1305,1255,1140,1
_{118 NMR (CDCl 3) δ:} 1.44 (18H, s, 2 × Bu t), 3.
17 (2H, dt, J = 2.0,6.2Hz, CH 2), 3.77 (2
H, t, J = 6.2 Hz, CH ₂ ), 5.49 (1 H, s, OH), 6.
84 (1H, t, J = 2.0 Hz, CH), 7.18-7.40 (5
H, m, 5 × aromatic-H), 7.59 (2H, s, 2 × aromatic
. -H) Elemental analysis _{(C 24 H 31 NO 3 S} × 0.1H 2 O) Calcd: C, 69.39; H, 7.61 ; N, 3.37; S, 7.
72 found: C, 69.28; H, 7.56; N, 3.39; S, 7.
69

Example 11 (R ³ = 4-chlorophenyl) (E) -2- (4-chlorophenyl) -5- (3,5-di-te
(rt-butyl-4-hydroxy) benzylidene-1,2-a
Sothiazolidine-1,1-dioxide (8k) and its (Z)
-Isomer (9k) Compound 6a (2.25 gr,
8.09 mmol) and N- (4-chlorophenyl) -1,2-
Isothiazolidine-1,1-dioxide 4k (2.34 gr,
(10.1 mmol) to give the adduct 7k. Yield 2.54 gr (62%). 7k of this adduct (2.53 g
r, 4.96 mmol) was treated with p-toluenesulfonic acid hydrate (250 mg) in toluene (70 ml) to give the desired compounds 8k and 9k. Yield 8k: 859 mg (39%); 9k: 263 mg
(12%)

8k: mp 245-246 ° C IR (KBr) cm ^-1 : 3560,2960,1644,159
_{2,1491,1430,1280,1105,1090 NMR (CDCl 3) δ:} 1.46 (18H, s, 2 × Bu t), 3.
30 (2H, dt, J = 2.6,6.6Hz, CH 2), 3.76 (2
H, t, J = 6.6 Hz, CH ₂ ), 5.55 (1 H, s, OH), 7.
28 (2H, s, 2 × aromatic-H), 7.26-7.40 (5
H, m, 4 × aromatic-H, CH). Elemental analysis (C ₂₄ H ₃₀ NO ₃ SCl) Calculated: C, 64.34; H, 6.75; N, 3.13; S, 7.
16; Cl, 7.91 Found: C, 64.59; H, 6.78; N, 3.28; S, 7.
17; Cl, 7.87 9k: mp 207-209 ° C IR (KBr) cm ^-1 : 3540, 2955, 1635, 159
5,1494,1432,1300,1270,1130 NMR (CDCl ₃ ) δ: 1.44 (18H, s, 2 × Bu ^t ), 3.
17 (2H, dt, J = 2.0,6.4Hz, CH 2), 3.73 (2
H, t, J = 6.4 Hz, CH ₂ ), 5.51 (1 H, s, OH), 6.
86 (1H, t, J = 2.0 Hz, CH), 7.34 (4H, s, 4 ×
aromatic-H), 7.57 (2H, s, 2 × aromatic-H). Elemental analysis (C ₂₄ H ₃₀ NO ₃ SCl) Calculated: C, 64.34; H, 6.75; N, 3 .13; S, 7.
16; Cl, 7.91 Found: C, 64.14; H, 6.80; N, 3.23; S, 7.
06, Cl, 7.95

Example 12 (R ³ = 2-pyridyl) (E) -2- (2-pyridyl) -5- (3,5-di-tert-butyl
(Tyl-4-hydroxy) benzylidene-1,2-isothia
Zolidine-1,1-dioxide (8 l) and its (Z) -isomer
Compound (91) According to a method similar to that in Example 1, compound 6a (208 mg,
0.75 mmol) and 4 l of N- (2-pyridyl) -1,2-isothiazolidine-1,1-dioxide (149 mg, 0.75 m
mol) to give 7 l of the adduct. Yield 233 mg (65%). 7 l of this adduct (231 mg, 0.485)
mmol) was treated with p-toluenesulfonic acid hydrate (60 mg) in toluene (5 ml) to give the desired compounds 8 l and 9 l. Yield 8 l: 96 mg (48%); 9 l: 19 mg (9%)

8l: mp 177-179 ° C IR (KBr) cm ^-1 : 3570, 2960, 1646, 160
0,1587,1472,1431,1300,1105,1
085 NMR (CDCl ₃ ) δ: 1.47 (18H, s, 2 × Bu ^t ), 3.
31 (2H, dt, J = 2.4, 6.8 Hz, CH ₂ ), 4.08 (2
H, t, J = 6.8 Hz, CH ₂ ), 5.55 (1 H, s, OH), 6.
99-7.05 (1H, m, CH), 7.28 (2H, s, 2 × arom
atic-H), 7.38 (1H, t, J = 2.4 Hz, Py-H),
7.55-7.74 (2H, m, 2 × Py-H), 8.33-8.
36 (1H, m, Py) .. Elemental analysis _{(C 23 H 30 N 2 O} 3 S) Calcd: C, 66.63; H, 7.29 ; N, 6.76; S, 7.
73 found: C, 66.31; H, 7.30; N, 6.72; S, 7.
669 l: mp 198-199 ° C IR (KBr) cm ^-1 : 3550,2960,1626,159
4,1570,1470,1429,1312,1302,1
_{. 272,1140,1115 NMR (CDCl 3) δ} : 1.46 (18H, s, 2 × Bu t), 3.
16 (2H, dt, J = 2.0,6.6Hz, CH 2), 4.06 (2
H, t, J = 6.6 Hz, CH ₂ ), 5.51 (1 H, s, OH), 6.
87 (1H, t, J = 2.0 Hz, CH), 6.96-7.04 (1
H, m, Py-H), 7.58 (2H, s, 2 x aromatic-H), 7.
54-7.73 (2H, m, 2 × Py-H), 8.32-8.37
. (1H, m, Py- H) Elemental analysis _{(C 23 H 30 N 2 O} 3 S) Calcd: C, 66.63; H, 7.29 ; N, 6.76; S, 7.
73 found: C, 66.40; H, 7.23; N, 6.71; S, 7.
53

Example 13 (R ³ = 3-pyridyl) (E) -2- (3-pyridyl) -5- (3,5-di-tert-butyl
(Tyl-4-hydroxy) benzylidene-1,2-isothia
Zolidine-1,1-dioxide (8m) Compound 6a (1.474 g) was prepared in the same manner as in Example 1.
r, 5.30 mmol) and N- (3-pyridyl) -1,2-isothiazolidine-1,1-dioxide 4m (1.051 gr, 5.51 mmol).
30 mmol) to give 7 m of the adduct.
Yield 1.522 gr (60%). 7m (1.522g)
(r, 3.19 mmol) was treated with p-toluenesulfonic acid hydrate (400 mg) in toluene (40 ml) to give the desired compound 8m. Yield 358 mg (27%) mp 207-209 ° C IR (KBr) cm ^-1 : 3625,3040,2960,164
_{0,1590,1480,1431,1305,1152 IR (CDCl 3) δ:} 1.47 (18H, s, 2 × Bu t), 3.3
6 (2H, dt, J = 2.4, 6.4 Hz, CH ₂ ), 3.84 (2H,
t, J = 6.4 Hz, CH ₂ ), 5.59 (1 H, s, OH), 7.29
(2H, s, 2 × aromatic-H), 7.29-7.40 (2H, m,
CH, Py-H), 7.84-7.93 (1H, m, Py-H), 8.
37-8.64 (2H, m, 2 × Py-H) Elemental analysis _{(C 23 H 30 N 2 O} 3 S) Calcd:. C, 66.63; H, 7.29; N, 6. 76; S, 7.
73 found: C, 66.31; H, 7.27; N, 6.69; S, 7.
47

Example 14 (R ³ = 4-pyridyl) (E) -2- (4-pyridyl) -5- (3,5-di-tert-butyl
(Tyl-4-hydroxy) benzylidene-1,2-isothia
Zolidine-1,1-dioxide (8n) Compound 6 (2.59 gr, 9.9 g) was prepared in the same manner as in Example 1.
36 mmol) and N- (4-pyridyl) -1,2-isothiazolidine-1,1-dioxide 4n (2.05 gr, 10.4 mmol)
The adduct 7n was obtained by aldol reaction with l). Yield 2.
721 gr (61%). This adduct 7n (1.65 gr, 3.46 m
mol) was treated with p-toluenesulfonic acid hydrate (433 mg) in toluene (80 ml) to give the desired compound 8n. Yield 65
8 mg (46%) mp 213-14.5 ° C. IR (KBr) cm ⁻¹ : 3400, 2955, 1643, 159
_{1,1502,1437,1316,1153 NMR (CDCl 3) δ:} 1.47 (18H, s, 2 × Bu t), 3.
37 (2H, dt, J = 2.2,6.8Hz, CH 2), 3.82 (2
H, t, J = 6.8 Hz, CH ₂ ), 5.61 (1 H, s, OH), 7.
21-7.25 (4H, m, 2 × aromatic-H, 2 × Py-
H), 7.42 (1H, t, J = 2.2 Hz, CH), 8.50-8.
58 (2H, m, 2 × Py-H) Elemental analysis _{(C 23 H 30 N 2 O} 3 S) Calcd: C, 66.63; H, 7.29 ; N, 6.76; S, 7 .
73 found: C, 66.46; H, 7.18; N, 6.66; S, 7.
49

[0066]

Embedded image

[0067]Example 15 (R^Three= H) (Y = CO_TwoC (C
H_Three)_Three)(E) -5- (3,5-di-tert-butyl-4-hydroxy
B) benzylidene-1,2-isothiazolidine-1,1-
Dioxide (10a) According to a method similar to that of Example 1, compound 6a and N- (tert
-Butoxycarbonyl) -1,2-isothiazolidine-
1,1-dioxide 4o (3-k according to the method of Reaction Scheme 1)
Propyl sulphonyl chloride and tert-butyl carb
(Prepared with rubamate as starting material)
P-Toluene was added to a toluene solution of the crude adduct 7o obtained by the reaction.
Sulfonic acid hydrate was added, and the mixture was heated under reflux for 45 minutes. Next
The reaction product is subjected to silica gel column chromatography.
And eluted from a mixture of n-hexane-ethyl acetate (2: 1)
The desired compound 10a was obtained from the above fraction. 8.5% yield of mp23
3-234 ° C IR (CHCl_Three)cm^-1: 3618,2952,1435,13
66,1311,1240,1155,1070 NMR (CDCl_Three) δ: 1.45 (18H, s, 2 × Bu^t), 3.
18 (2H, dt, J = 2.6,6.8Hz, CH_Two), 3.42-
3.60 (2H, m, CH_Two), 4.05-4.25 (1H, broad,
NH), 5.52 (1H, s, OH), 7.22-7.27 (3H,
m, 2 × aromatic-H, CH) Elemental analysis value (C₁₈H₂₇NO_ThreeS × 0.35H_TwoO) Calculated: C, 62.89; H, 8.12; N, 4.07; S, 9.
38 Found: C, 63.10; H, 7.90; N, 4.17; S, 9.
11

[0068]Example 16 (R^Three= H) (Y = 4-meth)
Xybenzyl)(Z) -5- (3,5-di-tert-butyl-4-hydroxy
B) benzylidene-1,2-isothiazolidine-1,1-
Dioxide (10b) The adduct 7h (1) of the aldol reaction obtained by the method of Example 8
3.16 gr, 25.3 mmol) in toluene solution (150 ml)
-Addition of toluene sulfonic acid hydrate (1.3 gr)
After heating to reflux for a minute, the reaction solution was passed through a small amount of silica gel.
And the solvent was distilled off under reduced pressure to give crude (E)-and (Z)-
2- (4-methoxybenzyl) -5- (3,5-di-tert-
(Butyl-4-hydroxy) benzylidene-1,2-isothienyl
Mixture of azolidine-1,1-dioxide 8h and 9h
(8.83 gr). A methylene chloride solution of this mixture (1
50 ml) and 4.1 ml of titanium tetrachloride at 30 ° C. at 0 ° C.
Stirred for minutes. The reaction product is subjected to silica gel column chromatography.
N-Hexane-ethyl acetate (1: 1) mixture
10a and 10b were obtained from the more eluted fractions. Yield 1
0a: 3.35 g (41%); 10b: 120 mg (1.5%). 10
a was consistent with the standard obtained in Example 15. 10b: mp161
-164 ° C IR (CHCl_Three)cm^-1: 3620,2954,1432,13
71,1312,1241,1157 NMR (CDCl_Three) δ: 1.45 (18H, s, 2 × Bu^t), 3.
11 (2H, dt, J = 2.1,6.7Hz, CH_Two), 3.39-
3.51 (2H, m, CH_Two), 4.26-4.40 (1H, broad,
NH), 5.49 (1H, s, OH), 6.80 (1H, t, J = 2.
1 Hz, CH), 7.55 (2 H, s, 2 × aromatic-H). Elemental analysis (C₁₈H₂₇NO_ThreeS) Calculated: C, 63.72; H, 8.08; N, 4.13; S, 9.
45 found: C, 63.64; H, 8.14; N, 4.06; S, 9.
36

Example 17 (R ³ ＨH) (Y = 3,4-dimethoxybenzyl) The aldol reaction adduct 7i (4.0 gr, 7.0 g) obtained in Example 9.
(3 mmol) in xylene solution (50 ml), 2,6-di-tert-butylphenol, anisole and p-toluenesulfonic acid hydrate were added in equimolar amounts, and the mixture was heated under reflux for 45 minutes, and the reaction product was subjected to silica gel column chromatography. Attached to 1
0a and 10b were obtained. Yield 10a: 580 mg (24%); 1
0b: 85 mg (3.5%). 10a and 10b are Example 15
And 16 were consistent with the standards obtained.

[0070]

Embedded image

Example 18 (R ³ ＣＨCH ₂ CO ₂ C ₂ H ₅ ) (E) -2-ethoxycarbonylmethyl-5- (3,5-di
-Tert-butyl-4-hydroxy) benzylidene-1,2
-Isothiazolidine-1,1-dioxide (8p) (E) -5- (3,5-di-tert-butyl-4-hydroxy) benzylidene-1,2-isothiazolidine-1,1-
Dioxide 10a (500 mg, 1.48 mmol), ethyl iodoacetate (240 μl, 2 mmol), 2N aqueous sodium hydroxide solution (1.5 ml, 3 mmol) and a small amount of N-benzyltrimethylammonium chloride in chloroform (20 ml) and water (1 ml)
0 ml) and stirred at room temperature for 24 hours. The product obtained by treating the reaction solution by a conventional method was purified by silica gel column chromatography to obtain the desired compound 8p. Yield 300 mg (49%) IR (CHCl ₃ ) cm ^-1 : 3620,2956,1747,14
35, 1298, 1229, 1160 NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.2 Hz, C
_{H 3), 1.45 (18H,} s, 2 × Bu t), 3.19 (2H, dt,
J = 2.6,6.6 Hz, CH ₂ ), 3.51 (2 H, t, J = 6.6)
Hz, CH ₂ ), 3.87 (2H, s, CH ₂ CO), 4.23 (2H,
q, J = 7.2 Hz, CH ₂ ), 5.52 (1 H, s, OH), 7.22
-7.30 (3H, m, 2 x aromatic-H, CH)

Example 19 (R ³ ＣＨCH ₂ COOH) (E) -2-carboxymethyl-5- (3,5-di-tert-
(Butyl-4-hydroxy) benzylidene-1,2-isothienyl
Azolidine-1,1-dioxide (8q) Compound 8p (610 m) obtained in the same manner as in Example 18.
g, 1.44 mmol) and a 2N aqueous solution of sodium hydroxide (1.
5 ml) was added to a mixture of THF (10 ml) and methanol (4 ml), and the mixture was stirred at 0 ° C. for 30 minutes.
(50 ml), washed with a 1N aqueous hydrochloric acid solution (20 ml) and then with a saturated saline solution (20 ml), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound 8q. Yield 4
45 mg (78%), mp 175-178 ° C IR (CHCl ₃ ) cm ^-1 : 3620,2954,1735,14
_{35,1297,1240,1149 NMR (CDCl 3) δ:} 1.45 (18H, s, 2 × Bu t), 3.
20 (2H, dt, J = 2.6,6.6Hz, CH 2), 3.51 (2
H, t, J = 6.6 Hz, CH ₂ ), 3.95 (2 H, s, CH ₂ C)
O), 5.54 (1H, s, OH), 7.25 (2H, s, 2 x aromat
ics-H) Elemental analysis _{(C 20 H 29 NO 5 S} ) Calculated: C, 60.46; H, 7.41 ; N, 3.53; S, 8.
07 Found: C, 60.34; H, 7.40; N, 3.56; S, 8.
04

Example 20 (R ³ ＣＨCH ₂ CH ₂ OH) (E) -2- (2-hydroxyethyl) -5- (3,5-di-
(tert-butyl-4-hydroxy) benzylidene-1,2-
Isothiazolidine-1,1-dioxide (8r) compound 10a (675 mg, 2 mmol), 2-iodoethanol
(624 μl, 8 mmol), 2N-sodium hydroxide aqueous solution
(2 ml) and a small amount of N-benzyltrimethylammonium chloride were added to a mixture of methylene chloride (20 ml) and water (10 ml), and the mixture was refluxed for 3 days. After treating the reaction solution by a conventional method, the product was subjected to silica gel column chromatography to obtain the desired compound 8r from a fraction eluted from a mixed solution of n-hexane-ethyl acetate (7: 3). Yield 190 mg (25
%), Mp 156-157 ° C IR (CHCl ₃ ) cm ^-1 : 3620,2950,1434,12
_{. 90,1240,1151,1066 NMR (CDCl 3) δ} : 1.45 (18H, s, 2 × Bu t), 3.
16 (2H, dt, J = 2.4, 6.5 Hz, CH ₂ ), 3.30 (2
_{H, m, CH 2),} 3.41 (2H, t, J = 6.5Hz, CH 2), 3.
87 (2H, t, J = 5.2Hz), 5.53 (1H, s, OH), 7.
23-7.29 (3H, m, 2 × aromatic-H, CH). Elemental analysis (C ₂₀ H ₃₁ NO ₄ S) Calculated: C, 62.96; H, 8.19; N, 3. 67; S, 8.
40 found: C, 62.72; H, 8.27; N, 3.69; S, 8.
21

Example 21 (R ³ ＣＨCH ₂ CH ₂ N (CH ₃ )
₂ ) (E) -2- (2-Dimethylamino) ethyl-5- (3,5-
Di-tert-butyl-4-hydroxy) benzylidene-1,
2-isothiazolidine-1,1-dioxide (8s) compound 10a (843 mg, 2.5 mmol), N, N-dimethyl-
2-bromoethylamine (750 mg, 5 mmol), 2N aqueous sodium hydroxide solution (3 ml, 6 mmol) and a small amount of N chloride
Benzyltrimethylammonium in chloroform (3
0 ml) and water (10 ml), and the mixture was stirred for 2 hours under ice-cooling. The chloroform layer was washed with water (20 ml × 2) and dried over anhydrous sodium sulfate. Chloroform was distilled off under reduced pressure to obtain the target compound as a crystalline residue. Yield 950 mg (9
3%), mp 160-165 ° C IR (CHCl ₃ ) cm ^-1 : 3620,2956,1435,12
_{. 90,1148 NMR (CDCl 3) δ} : 1.45 (18H, s, 2 × Bu t), 2.
29 (6H, s, N (CH ₃ ) ₂ ), 2.60 (2H, t, J = 6.6H
z, CH ₂ ), 3.12 (2H, dt, J = 2.2,6.6Hz, C
_{H 2), 3.20 (2H,} t, J = 6.6Hz, CH 2), 3.38 (2
H, t, J = 6.6 Hz, CH ₂ ), 5.51 (1 H, s, OH), 7.
21-7.28 (3H, m, 2 × aromatic-H, CH). Elemental analysis (C ₂₂ H ₃₆ N ₂ O ₃ S × 0.2 CH ₂ Cl ₂ ) Calculated: C, 62.65; H , 8.62; N, 6.58; S, 7.
53; Cl, 3.33 Found: C, 62.32; H, 8.60; N, 6.71; S, 7.
56; Cl, 3.24

Example 22 (R ³ ＣＯCOCH ₃ ) (E) -2-acetyl-5- (3,5-di-tert-butyl-
4-hydroxy) benzylidene-1,2-isothiazolidy
1,1-dioxide (8t) Compound 10a (585 mg, 1.74 mmol) in pyridine (1
(0 ml), a small amount of 4-N, N-dimethylaminopyridine was added, 6 ml of acetic anhydride was added dropwise under ice cooling, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, filtered through a small amount of silica gel, and the solvent was concentrated under reduced pressure to obtain the target compound as a crystalline residue.
Yield 360 mg (55%), mp 177-179 ° C IR (CHCl ₃ ) cm ^-1 : 3618,2958,1695,14
_{35,1379,1297,1153,1117 NMR (CDCl 3) δ:} 1.46 (18H, s, 2 × Bu t), 2.
53 (3H, s, COCH ₃ ), 3.20 (2H, dt, J = 2.2,
7.0 Hz, CH ₂ ), 3.86 (2 H, t, J = 7.0 Hz, C
H ₂ ), 5.60 (1H, s, OH), 7.52 (2H, s, 2 × aroma
tic-H), 7.39 (1 H, t, J = 2.2 Hz, CH). Elemental analysis (C ₂₀ H ₂₉ NO ₄ S) Calculated: C, 63.30; H, 7.70; N , 3.69; S, 8.
45 found: C, 63.27; H, 7.83; N, 3.64; S, 8.
22

Example 23 (R ³ = N-methyl-N-methoxy) (E) -2- (N-methyl-N-methoxy) carbamoyl-
5- (3,5-di-tert-butyl-4-hydroxy) ben
Dylidene-1,2-isothiazolidine-1,1-dioxy
(8u) compound 10a (450 mg, 1.33 mmol) and N-methyl-
N-methoxy-O-phenyl carbamate (300 mg,
1.66 mmol) was dissolved in a mixed solution of THF (10 ml) and HMPA (10 ml), and the mixture was cooled to −40 ° C. with stirring to obtain a THF solution of lithium hexamethyldisilazane (LiHMDS) (1M, 3.
(2 ml) was added dropwise, and the reaction solution was warmed to room temperature. The reaction solution was poured into a 1N aqueous hydrochloric acid solution (20 ml) and ethyl acetate (3 mL) was added.
0 ml), and the ethyl acetate layer was washed with water (30 ml) and saturated saline (30 ml), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, and 8u of the desired compound was obtained from the fraction eluted with a mixed solution of n-hexane-ethyl acetate (7: 3). Yield 23
0 mg (41%) IR (CHCl ₃ ) cm ^-1 : 3620,2958,1673,14
35,1388,1330,1240,1207,1155,
_{1092. NMR (CDCl 3) δ:} 1.45 (18H, s, 2 × Bu t), 3.
21 (2H, dt, J = 2.2, 6.8 Hz, CH ₂ ), 3.31 (3
H, s, NCH ₃ ), 3.78 (3H, s, OCH ₃ ), 3.89 (2
H, t, J = 6.8 Hz), 5.54 (1 H, s, OH), 7.23 (2
H, s, 2 × aromatic-H), 7.31 (1H, t, J = 2.2H
z, CH)

[0077]Example 24 (R^Three= N-benzyloxy
-N-methoxymethyl)(E) -2- (N-benzyloxy-N-methoxymethyl)
Carbamoyl-5- (3,5-di-tert-butyl-4-hi
(Droxy) benzylidene-1,2-isothiazolidine-
1,1-dioxide (8v) Compound 10a (424 mg, 1.26 mmol) and N-benzyl
Roxy-N-methoxymethyl-O-phenylcarbame
(722 mg, 2.52 mmol) in the same manner as in Example 23
In a mixture of THF (90 ml) and HMPA (30 ml)
Treated with a solution of iHMDS in THF (1M, 4.0ml) and reacted
The product is subjected to silica gel chromatography to give n-hex.
From the fraction eluted with a mixture of sun and ethyl acetate (3: 1)
Compound 8v was obtained. Yield 600 mg (90%) NMR (CDCl_Three) δ: 1.45 (18H, s, 2 × Bu^t), 3.
18 (2H, dt, J = 2.0,6.8Hz, CH_Two), 3.45 (3
H, s, OCH_Three), 3.79 (2H, t, J = 6.8Hz, CH_Two),
4.94 (2H, s, OCH_Two), 5.02 (2H, s, OCH_Two),
5.54 (1H, s, OH), 7.22 (2H, s, 2 × aromatic-
H), 7.30 (1H, t, J = 2.0 Hz, CH), 7.30-7.
55 (5H, m, 5 x aromatic-H).

Example 25 (R ³ ＣＯCONOHH) (E) -2- (hydroxycarbamoyl) -5- (3,5-di
-Tert-butyl-4-hydroxy) benzylidene-1,2
-Isothiazolidine-1,1-dioxide (8w) A solution of compound 8v (600 mg, 1.13 mmol) obtained in Example 24 in methylene chloride (8 ml) was added with titanium tetrachloride (5 ml) under ice-cooling.
00 μl, 4.56 mmol) and stirred for 1.5 hours. A 2N aqueous solution of hydrochloric acid (10 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with methylene chloride (20 ml). did. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, and the desired compound 8w was obtained from the fraction eluted with a mixed solution of n-hexane-ethyl acetate (1: 1). Yield 150 mg (33%) IR (CHCl ₃ ) cm ^-1 : 3618,2956,1707,14
_{. 34,1320,1151,1100 NMR (CDCl 3) δ} : 1.45 (18H, s, 2 × Bu t), 3.
23 (2H, dt, J = 2.2, 7.0 Hz, CH ₂ ), 3.94 (2
H, t, J = 7.0 Hz, CH ₂ ), 5.61 (1 H, s, OH), 6.
85-6.95 (1H, broad, OH), 7.24 (2H, s, 2 ×
aromatic-H), 7.30 (1H, t, J = 2.2Hz, CH),
8.61 (1H, s, NH).

[0079]

Embedded image

Example 26 (E) -2-hydroxy-5- (3,5-di-tert-butyl)
(4-hydroxy) benzylidene-1,2-isothiazo
Lysine-1,1-dioxide (11a) and its (Z) -isomer
Compound (11b) Compound 6a was subjected to an aldol reaction with N-benzyloxy-1,2-isothiazolidine-1,1-dioxide in the same manner as in Example 1, and then the aldol reaction adduct was converted to p-toluenesulfonic acid. The crude 2-benzyloxy-5- (3,5-di-tert-butyl-4-hydroxy) benzylidene-1,2-isothiazolidine-1,1-dioxide (4. 44 g, 10 mmol) in methylene chloride solution (80 ml) under ice-cooling and stirring.
(4.4 ml, 40 mmol) was added dropwise, and stirring was continued at the same temperature for 2 hours. A 1N aqueous hydrochloric acid solution (50 ml) was added to the reaction solution, the methylene chloride layer was separated, and water (50 ml) and saturated saline (5 ml) were added.
0 ml) and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the target compounds 11b and 11a were sequentially obtained from the fraction eluted with a mixed solution of n-hexane-ethyl acetate (3: 1).

Yield 11a: 1.6 gr (45%); 11b: 178
mg (5%) 11a: mp 177-182 ° C. (d) IR (KBr) cm ⁻¹ : 3560,3430,1425,133
_{0,1240,1155,1130,1115 NMR (CDCl 3) δ:} 1.45 (18H, s, 2 × Bu t), 3.
18 (2H, dt, J = 2.6,6.8Hz, CH 2), 3.89 (2
H, t, J = 6.8 Hz, CH ₂ ), 5.56 (1 H, s, OH), 6.
18-6.30 (1H, broad, OH), 7.26-7.35 (3
H, m, 2 × aromatic-H, CH) Elemental analysis (C ₁₈ H ₂₇ NO ₄ S) Calculated: C, 61.16; H, 7.70; N, 3.96; S, 9.
07 Found: C, 60.86; H, 7.68; N, 3.93; S, 8.
90 11b: mp 190-198 ° C (d) IR (CHCl ₃ ) cm ^-1 : 3622,3540,3020,29
_{54,1632,1431,1340,1241,1157 NMR (CDCl 3) δ:} 1.45 (18H, s, 2 × Bu t), 3.
17 (2H, dt, J = 2.2,6.8Hz, CH 2), 3.62 (2
H, m, CH ₂ ), 5.51 (1H, s, OH), 6.22 (1H, s, O
H) 7.04 (1H, t, J = 2.2 Hz, CH), 7.49 (2H,
s, 2 × aromatic-H) Elemental analysis (C ₁₈ H ₂₇ NO ₄ S) Calculated: C, 60.16; H, 7.70; N, 3.96; S, 9.
07 Found: C, 60.67; H, 7.58; N, 3.96; S, 8.
87

Example 27 (E) -2-Isopropyl-5- (3,5-di-tert-butyl
Tyl-4-hydroxy) benzylidene-1,2-isothi
Azolidine-1,1-dioxide (8x)

Embedded image According to the method of Example 1, N-isopropyl-1,2-
Isothiazolidine-1,1-dioxide 4p (3.
65 gr, 22.4 mmol) and 3,5-di-tert-butyl-4-methoxymethoxybenzaldehyde (6a)
(5.28 gr, 19.0 mmol) to give the adduct (7p) as a white powder. Yield 6.27
gr (74.7%). This aldol adduct 7p (6.2
7 gr) was dissolved in toluene (120 ml), p-toluenesulfonic acid hydrate (600 mg) was added, and the mixture was heated under reflux for 30 minutes. After cooling, the reaction solution was washed twice with water (100 ml). After drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. The crystalline residue was recrystallized from methanol to obtain the target compound as colorless columnar crystals. Yield 2.16 gr (30
%). 8x: mp 148-150 ° C IR (KBr) cm ^-1 : 3550, 2960, 164
_{5,1600,1432,1273,1173 NMR (CDCl 3) δ:} 1.29 (6H, d, J =
6.6 Hz, 2 × CH ₃ ), 1.45 (18 H, s, 2
× Bu ^t ), 3.07-3.14 (2H, m, C
_{H 2), 3.29~3.35 (2H,} m, CH 2),
3.94 (1H, sept, CH), 5.48 (1H,
s, OH), 7.22 (1H, t, J = 2.8 Hz, C
H), 7.23 (2H, s , Ar-H) Elemental analysis _{(C 21 H 33 NO 3 S} ) Calcd: C, 66.45; H, 8.76 ; N, 3.6
9; S, 8.45 Found: C, 66.37; H, 9.01; N, 3.6.
7; S, 8.28

Example 28 (E) -2-Ethyl-5- (3,5-dimethyl-4-high
(Droxy) benzylidene-1,2-isothiazolidine-
1,1-dioxide (8y)

Embedded image According to the method of Example 1, N-ethyl-1,2-isothiazolidine-1,1-dioxide 4a (2.5 gr, 1
6.8 mmol) and 3,5-dimethyl-4-methoxymethoxybenzaldehyde (6b) (2.92 gr, 15 mm)
ol) to give the adduct (7q) as a white powder. Yield 4.01 gr (77.8%). This aldol adduct 7q (3.75 gr, 10.9 mmol) was dissolved in toluene (100 ml), p-toluenesulfonic acid hydrate (200 mg) was added, and the mixture was heated under reflux for 30 minutes and cooled. After that, wash twice with water (100 ml),
After drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. The crystalline residue was recrystallized from methanol to obtain the target compound as colorless columnar crystals. Yield 1.63 gr (53%). 8y: mp 167-168 ° C IR (Nujol) cm ^-1 : 3399, 1641, 159
3,1489,1461,1272,1217,117
0,1145,1128 NMR (CDCl ₃ ) δ: 1.29 (3H, t, J =
7.4 Hz, CH ₃ ), 2.26 (6 H, s, 2 × CH
₃ ), 3.05 to 3.36 (6H, m, 2 × CH ₂ , N
CH ₂ ), 5.00 (1H, broad, OH), 7.
04 (2H, s, Ar-H), 7.15 (1H, t, J
= 2.8 Hz, CH) Elemental analysis _{(C 14 H 19 NO 3 S} ) Calcd: C, 59.76; H, 6.81 ; N, 4.9
8; S, 11.39 Found: C, 59.56; H, 6.85; N, 4.9.
9; S, 11.38

Example 29 (E) -2-Ethyl-5- (3,5-diisopropyl-4
-Hydroxy) benzylidene-1,2-isothiazoly
Gin-1,1-dioxide (8z)

Embedded image Using the same method as in Example 1, N-ethyl-1,2-isothiazolidine-1,1-dioxide 4a (4.9 g) was used.
r, 32.8 mmol) and 3,5-diisopropyl-4-methoxymethoxybenzaldehyde (6c) (7.51 g)
r, 30 mmol) by the aldol reaction.
r) was obtained as a white powder. Yield 6.07 gr (50.6
%). This aldol adduct 7r (5.0 gr, 20 mmol)
Was dissolved in toluene (100 ml), p-toluenesulfonic acid hydrate (200 mg) was added, and the mixture was heated under reflux for 30 minutes. Dry over sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crystalline residue, which was recrystallized from methanol to obtain the target compound 8z as colorless columnar crystals. Yield 3.24 gr
(48%). 8z: mp 167-168 ° C IR (Nujol) cm ^-1 : 3413, 1644, 160
0,1472,1276,1194,1153,111
5 NMR (CDCl ₃ ) δ: 1.27 (12H, d, J =
6.6 Hz, 2 × CH (CH ₃ ) ₂ ), 3.06 to 3.3
6 (8H, m, 3 × CH ₂ , 2 × CH), 5.13 (1
H, s, CH), 7.12 (2H, s, Ar-H), 7.24
(1H, t, J = 2.8 Hz, CH) Elemental analysis (C ₁₈ H ₂₇ NO ₃ S) Calculated: C, 64.06; H, 8.07; N, 4.1
5; S, 9.50 Found: C, 64.03; H, 8.02; N, 4.1.
1: S, 9.46

Example 30 (E) -2-Ethyl-5- (3,5-dimethoxy-4-ha
(Idroxy) benzylidene-1,2-isothiazolidine
-1,1-dioxide (8Ia)

Embedded image N-ethyl-1,2-isothiazolidine-1,1-dioxide 4a (5.22 g) was obtained in the same manner as in Example 1.
r, 35 mmol) and 3,5-dimethoxy-4-methoxymethoxybenzaldehyde (6d) (6.77 gr, 3
0 mmol) to give the adduct 7s as a white powder. Yield 8.42 gr (74.8%). This aldol adduct 7s (4.28 gr, 11.4 mmol) was dissolved in toluene (100 ml), p-toluenesulfonic acid hydrate (200 mg) was added, and the mixture was heated under reflux for 30 minutes. After cooling, it is washed twice with water (100 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crystalline residue was recrystallized from methanol to obtain the target compound 8Ia as colorless needles. Yield 1.64 gr (4
6%). 8Ia: mp164-166 ° C IR (Nujol) cm ^-1 : 3434,1643,160
7, 1593, 1517, 1454, 1321, 127
3,1251,1219,1172,1149,110
9 NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.4)
Hz, CH ₃ ), 3.10 to 3.37 (6H, m, 3 ×
CH ₂ ), 3.92 (6H, s, 2 × OCH ₃ ), 5.76
(1H, s, OH), 6.65 (2H, s, Ar-H),
7.20 (1 H, t, J = 2.8 Hz, CH) Elemental analysis (C ₁₄ H ₁₉ NO ₅ S) Calculated: C, 53.66; H, 6.11; N, 4.4
7; S, 10.23 Found: C, 53.45; H, 6.06; N, 4.4
4: S, 10.33

Example 31 (E) -2-Ethyl-5- (3-methoxy-4-hydro
Xy) benzylidene-1,2-isothiazolidine-1,1
-Dioxide (8Ib)

Embedded image N-ethyl-1,2-isothiazolidine-1,1-dioxide 4a (5.00 g) was prepared in the same manner as in Example 1.
r, 33.5 mmol) and 3-methoxy-4-methoxymethoxybenzaldehyde (6e) (5.88 gr, 30 m)
mol) to give the adduct 7t as a white powder. Yield 4.35 gr (42%). The aldol adduct 7t (4.30 gr, 12.4 mmol) was dissolved in toluene (100 ml), p-toluenesulfonic acid hydrate (200 mg) was added, and the mixture was heated under reflux for 30 minutes.
The reaction solution is washed twice with water (200 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, the fraction eluted with n-hexane: ethyl acetate (2: 1) was isolated, and recrystallized from a methylene chloride: diisopropyl ether mixture to give the desired compound as colorless columnar crystals. Obtained. Yield 2.7 gr (31.
8%). 8Ib: mp 146-148 ° C. IR (Nujol) cm ⁻¹ : 3404, 2924, 164
6,1611,1594,1516,1462,127
0,1149,1130 NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.4)
Hz, CH ₃ ), 3.08-3.18 (2H, m, C
H ₂ ), 3.17 (2H, q, J = 7.4 Hz, 2 × CH
_{2), 3.26 ~ 3.34 (2H} , m, CH 2), 3.92
(3H, s, OCH ₃ ) 5.88 (1H, s, OH), 6.
86-7.02 (3H, m, Ar-H), 7.21 (1
H, t, J = 2.8 Hz , CH) Elemental analysis _{(C 13 H 17 NO 4 S} ) Calculated: C, 55.11; H, 6.05 ; N, 4.9
4; S, 11.32 Found: C, 54.75; H, 6.11; N, 4.9.
9; S, 11.23

Example 32 (E) -2-Ethyl-5- (4-hydroxy) benzylide
1,2-isothiazolidine-1,1-dioxide
(8Ic)

Embedded image N-ethyl-1,2-isothiazolidine-1,1-dioxide 4a (3.28) was prepared in the same manner as in Example 1.
gr, 22 mmol) and 4-methoxymethoxybenzaldehyde (6f) (3.32 gr, 20 mmol) to give the adduct 7u as a white powder. Yield 4.10 gr (65%). This aldol adduct 7u (4.
00 gr, 12.7 mmol) was dissolved in toluene (100 ml), and p-toluenesulfonic acid hydrate (200 mg) was dissolved.
Was added and heated under reflux for 30 minutes.
ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with n-hexane: ethyl acetate (3: 2) was isolated. Methylene chloride: diisopropyl ether
Recrystallization from the tellurium mixture gave the target compound as colorless columnar crystals. Yield 1.0 gr (31.1%) 8Ic: mp 135-138 ° C IR (Nujol) cm ^-1 : 3346,2914,164
6,1605, 1584, 1513, 1453, 137
6,1282,1223,1136 NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.2)
_{Hz, CH 3), 3.04~ 3.12} (2H, m, C
H ₂ ), 3.17 (2H, q, J = 7.2 Hz, CH ₂ ),
3.27 ~ 3.33 (2H, m, CH 2), 5.59 (1
H, s, OH), 6.85 to 6.90 (2H, m, Ar-
H), 7.19 (1H, t, J = 2.8 Hz, CH), 7.
24 ~ 7.30 (4H, m, Ar-H) Elemental analysis _{(C 12 H 15 NO 3 S} ) Calcd: C, 56.90; H, 5.97 ; N, 5.5
3: S, 12.66 Found: C, 56.74; H, 5.98; N, 5.5.
2; S, 12.41

Example 33 (E) -2- (3,5-di-tert-butyl-4-hydroxy
B) benzylidene sulfolane (8Id)

Embedded image Sulfolane 4q (2.4) was prepared in the same manner as in Example 1.
gr, 20 mmol) and 3,5-di-tert-butyl-4-
Methoxy methoxybenzaldehyde 6a (5.57 gr,
Aldol reaction with 20 mmol) gave the adduct 7v as a white powder. Yield 5.58 gr (70%). This aldol adduct 7v (4.00 gr, 10.0 mmol) was dissolved in toluene (100 ml), p-toluenesulfonic acid hydrate (200 mg) was added, and the mixture was heated under reflux for 30 minutes. (200 ml), dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the fraction eluted with n-hexane: ethyl acetate (3: 1) was collected. Collection, concentration under reduced pressure, n-
Recrystallization from a hexane: ether mixture gave the target compound as colorless columnar crystals. Yield 1.346 gr (40%). 8Id: mp 152-154 ° C IR (Nujol) cm ^-1 : 3608, 2914, 163
8,1597,1461,1376,1285,121
4,1133 NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × Bu
^{t), 2.31 (2H, q} , J = 7 Hz, CH 2), 3.0
0 to 3.07 (4H, m, 2 × CH ₂ ), 5.51 (1
H, s, OH), 7.22 (1H, t, J = 2.6 Hz, C
H), 7.26 (2H, s , Ar-H) Elemental analysis _{(C 19 H 28 O 3 S} ) Calcd: C, 67.82; H, 8.38 ; S, 9.53 Found: C, 67.90; H, 8.38; S, 9.34.

Example 34 (E) -6- (3,5-Di-tert-butyl-4-hydro
Xy) benzylidene-2-methyl-4,5-dihydro-
6H-1,3,2-thiaoxazine-1,1-dioxa
Id (8Ie)

Embedded image In the same manner as in Example 1, N-methyl-1,3,2-
Thioxazine-1,1-dioxide 4r (575
mg, 3.80 mmol) and 3,5-di-tert-butyl-4-methoxymethoxybenzaldehyde 6a (84
6 mg, 3.04 mmol) to give the adduct 7w as a white powder. Yield 1.458 gr. This aldol adduct 7w (1.458 gr) was dissolved in toluene (50
dissolved in p-toluenesulfonic acid hydrate (1 ml).
After heating under reflux for 30 minutes, the reaction product was subjected to silica gel column chromatography, and the target compound was converted into colorless crystals from the fraction eluted with a mixed solution of n-hexane: ethyl acetate (6: 1). Obtained. Yield 511 mg (4
3%). 8Ie: mp 215-16.5 ° C. IR (KBr) cm ⁻¹ : 3599, 3438, 296
0,1637,1599,1437,1326,129
8,1153 NMR (CDCl ₃ ) δ: 1.44 (18H, s, 2 ×
^{Bu t), 3.00 (3H,} s, CH 3), 3.26 ~ 3.
32 (2H, m, CH ₂ ), 4.12 to 4.17 (2H,
m, CH ₂ ), 5.49 (1H, s, OH), 7.15 (2
H, s, Ar-H), 7.55 (1H, broad, CH) Elemental analysis (C ₁₉ H ₂₉ NO ₄ S) Calculated: C, 62.10; H, 7.95; N, 3. 8
1; S, 8.72 Found: C, 62.03; H, 7.91; N, 3.9
2; S, 8.51

Example 35 (E) -6- (3,5-Di-tert-butyl-4-hydro
Xy) benzylidene-2-methoxy-3,4,5,6-
Tetrahydro-1,2-thiazine-1,1-diox
Side (8If)

Embedded image N-methoxy-3,4,4 was prepared in the same manner as in Example 1.
5,6-tetrahydro-1,2-thiazine-1,1
Adduct 7x by aldol reaction with dioxide 4s (2.73 gr, 16.5 mmol) and 3,5-di-tert-butyl-4-methoxymethoxybenzaldehyde 6a (5.0 gr, 18 mmol) Obtained. Yield 7.3 gr. To a toluene solution (100 ml) of the aldol adduct 7x (2.1 gr, 4.73 mmol) was added p-toluenesulfonic acid hydrate (200 mg), and the mixture was heated under reflux for 30 minutes, and the reaction product was silica gel. Subjected to column chromatography,
The target compound was obtained as a brown powder from the fraction eluted with a mixed solution of n-hexane: ethyl acetate (4: 1). Yield 750 m
g (42%). IR (CHCl ₃ ) cm ^-1 : 3618,2950,163
0, 1435, 1340, 1238, 1161 NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × B
u ^t ), 1.80-1.95 (2H, m, CH ₂ ), 3.0
4 (2H, t, J = 6.0, Hz, CH 2), 3.77 ~
3.83 (2H, m, CH ₂ ), 3.80 (3H, s, OC
H ₃ ), 5.46 (1H, s, OH), 7.20 (2H, s, OH)
Ar-H), 7.46 (1H, s, CH)

Example 36 (E) -5- (3,5-Di-tert-butyl-4-hydro
Xy) benzylidene-2-ethyl-1,2-isothiazo
Lysin-3-one-1,1-dioxide (8 Ig) (1) (3,5-di-tert-butyl-4-methoxymethoate)
(Xybenzoyl) -N-ethyl-N-diphenylmethyl
Methanesulfonamide (14)

Embedded image

N-ethyl-N-diphenylmethylmethanesulfonamide ( 12 ) is prepared by reacting methanesulfonyl chloride with diphenylmethylamine in the presence of triethylamine, followed by the reaction of ethyl iodide in the presence of potassium carbonate. It was synthesized by acting.
3,5-di-tert-butyl-4-methoxymethoxy-N
-Methyl-N-methoxybenzamide ( 13 ) is 3,5
-Di-tert-butyl-4-hydroxybenzoic acid was converted into an acid chloride by a conventional method, reacted with N, O-dimethylhydroxylamine, and synthesized by methoxymethylation of a phenolic hydroxyl group. The compound ( 12 ) (1
6.82 g (58 mmol) in THF (200 ml) was added to -5.
The mixture was cooled to 0 ° C or lower, a THF solution of lithium bistrimethylsilylamide (1.0 M) (64 ml, 64 mmol) was slowly added dropwise, and the mixture was stirred at -50 ° C for 30 minutes. Then the compound
A solution of ( 13 ) (17.7 g, 52.2 mmol) in THF (100 m
l) was slowly added dropwise under the same conditions, washed with THF (30 ml), the reaction system was warmed to room temperature, saturated aqueous ammonium chloride (500 ml) was added, and the mixture was extracted with ethyl acetate (400 ml). I do. The separated organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (500 ml) and a saturated saline solution (500 ml), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and purified by elution with n-hexane-ethyl acetate (9: 1 to 7: 1).
14 was obtained as a colorless oil. Yield 27.2 g (92%) IR (CHCl ₃ ) cm ^-1 : 2960,1673,1339,11
88 NMR (CDCl ₃ ) δ: 0.83 (3H, t, J = 7.0 Hz,
CH ₃ ), 1.45 (18H, s, 2 × ^t Bu), 3.56 (2H,
q, J = 7.0 Hz, CH ₂ ), 3.65 (3 H, s, CH ₃ ), 4.
_{37 (2H, s, CH 2} ), 6.42 (1H, s, CH), 7.31
~ 7.38 (10H, m, 10 x aromatic-H), 7.89
(2H, s, 2 × aromatic-H)

(2) tert-butyl 3- (3,5-di-
tert-butyl-4-methoxymethoxybenzoyl) -3
-(N-ethyl-N-diphenylmethylsulfamoyl)
Propionate (15)

Embedded image (3,5-di-tert-butyl-4-methoxymethoxybenzoyl) -N-ethyl-N-diphenylmethylmethanesulfonamide ( 14 ) (27.0 g, 47.7 mmol), tert
-Butyl bromoacetate (9.25 ml, 57.3 mmol)
And potassium carbonate (9.89 g, 71.6 mmol) in DM
The suspension of F (300 ml) was stirred at room temperature for 18 hours, 600 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (800 ml).
The organic layer was separated, and water (300 ml) and saturated saline (500 ml)
And dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a pale yellow solid. This was thoroughly washed with n-hexane and concentrated under reduced pressure to obtain 15 as a colorless powder. Yield 26.75 g (82%). mp. 104 ~
105 ° C IR (KBr) cm ^-1 : 3435,1735,1677,134
0,1164,1147 NMR (CDCl ₃ ) δ: 0.77 (3H, t, J = 7.0 Hz,
CH ₃ ), 1.21 (9H, s, ^t Bu), 1.44 (18H, s, 2
× ^t Bu), 2.83 (1 H, dd, J = 3.2, 16.8 Hz, C
H ₂ × 1/2), 3.29 to 3.51 (3H, m, CH ₂ + CH
₂ × 1/2), 3.65 (3H, s, CH ₃ ), 4.90 (2H, s,
CH ₂ ), 5.28 (1H, dd, J = 3.2, 10.4 Hz, C
H), 6.39 (1H, s, CH), 7.31 to 7.34 (10
H, m, 10 × aromatic-H), 7.96 (2H, s, 2 × aroma)
tic-H) Elemental analysis _{(C 39 H 53 NO 7 S} ) Calcd C, 68.90; H, 7.86; N, 2.06; S,
4.72 found C, 68.80; H, 7.93; N, 2.16; S,
4.55

(3) tert-butyl 4- (3,5-di-
tert-butyl-4-methoxymethoxyphenyl) -4-
Hydroxy-3- (N-ethyl-N-diphenylmethyl
Sulfamoyl) butyrate (16)

Embedded image tert-butyl 3- (3,5-di-tert-butyl-4
-Methoxymethoxybenzoyl) -3- (N-ethyl-N
-Diphenylmethylsulfamoyl) propionate ( 1
5 ) To a solution of (22.6 g, 33.2 mmol) in MeOH (180 ml) and CH ₂ Cl ₂ (180 ml) was added sodium borohydride (1.89 g, 49.9 mmol) little by little under ice-cooling. After heating to room temperature, the mixture is stirred for 45 minutes. 5 ml of acetone was added to the reaction solution, and a saturated aqueous solution of ammonium chloride was added to 4 ml of the reaction solution.
Add 00 ml and extract with methylene chloride (400 ml). The organic layer was separated, washed with water (400 ml) and saturated saline (400 ml), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a pale pink solid, which was thoroughly washed with n-hexane to obtain 16 as a colorless powder. Yield 21.
8g (96%) IR (KBr) cm ^-1 : 3499,2970,1737,160
0,1319,1151 NMR (CDCl ₃ ) δ: 0.84 (3H, t, J = 7.0 Hz,
CH ₃ ), 1.21 (9H, s, ^t Bu), 1.41 (18H, s, 2
× ^t Bu), 2.22 (1H, dd, J = 6.6, 17.6Hz, C
H ₂ × 1/2), 2.48 (1H, dd, J = 4.2, 17.6)
_{Hz, CH 2 × 1/2} ), 3.37~3.58 (2H, m, C
_{H 2), 3.62 (3H,} s, CH 3), 3.92~4.07 (1
H, m, CH), 4.14 (1H, d, J = 2.2Hz, OH),
_{4.86 (2H, s, CH 2} ), 4.97 (1H, dd, J = 2.
2,9.2 Hz, CH), 6.47 (1H, s, CH), 7.19
(2H, s, 2 × aromatic-H), 7.32 to 7.34 (10
H, m, 10 × aromatic-H) Elemental analysis (C ₃₉ H ₅₅ NO ₇ S · 0.7H ₂ O) Calculated C, 67.44; H, 8.18; N, 2.02; S,
4.62 found C, 67.50; H, 8.06; N, 2.15; S,
4.51

(4) tertbutyl 4- (3,5-di-te
rt-butyl-4-methoxymethoxyphenyl) -4-h
Droxy-3- (N-ethylsulfamoyl) butyrate
(17)

Embedded image tert-butyl 4- (3,5-di-tert-butyl-4-methoxymethoxyphenyl) -4-hydroxy-3- (N-
A suspension of ethyl (N-diphenylmethylsulfamoyl) butyrate ( 16 ) (20.8 g, 30.5 mmol) and palladium hydroxide-carbon (3.05 g) in THF (100 ml) in methanol (200 ml) was treated with hydrogen Stir at room temperature under an atmosphere for 5 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated.
The residue was recrystallized from ether-n-hexane to give 17 . Yield 13.69 g (87%) mp. 96-
97 ° C IR (KBr) cm ^-1 : 3441,3298,2966,173
6,1635,1367,1152 NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.4Hz,
CH ₃ ), 1.36 (9H, s, ^t Bu), 1.44 (18H, s, 2
× ^t Bu), 2.31 (1H, dd, J = 5.6, 17.6Hz, C
H ₂ × 1/2), 2.80 (1H, dd, J = 6.6, 17.6)
_{Hz, CH 2 × 1/2} ), 3.00~3.27 (2H, m, C
_{H 2), 3.40 (1H,} d, J = 4.8Hz, OH), 3.64
_{(3H, s, CH 3)} , 3.97 (1H, ddd, J = 5.6,6.
6,8.2 Hz, CH), 4.19-4.25 (1 H, m, N
H), 4.89 (2H, s , CH 2), 4.95 (1H, dd, J =
4.8, 8.2 Hz, CH), 7.27 (2 H, s, 2 × aromati
c-H) Elemental analysis _{(C 26 H 45 NO 7 S} ) Calcd C, 60.56; H, 8.80; N, 2.72; S,
6.22 found C, 60.37; H, 8.72; N, 2.69; S,
6.17

(5) 5- (3,5-di-tert-butyl- )
4-hydroxyphenyl) -4- (N-ethylsulfamo
Yl) -γ-butyrolactone (18)

Embedded image tert-butyl 4- (3,5-di-tert-butyl-4-methoxymethoxyphenyl) -4-hydroxy-3- (N-
Ethyl sulfamoyl) butyrate ( 17 ) (1.10 g,
To a chloroform solution (30 ml) of 2.13 mmol) was added iodotrimethylsilane (TMSI) (0.91 ml,
6.39 mmol) at once and stir at the same temperature for 30 minutes.
A 5% aqueous solution of sodium thiosulfate (70 ml) was added to the reaction solution, and the mixture was extracted twice with methylene chloride (60 ml). The combined organic layer was washed twice with a saturated saline solution (70 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography eluting with n-hexane-ethyl acetate (3: 1) to obtain 18 as a colorless solid. Yield 481 mg (57%) mp. 129-131 ° C IR (CHCl ₃ ) cm ^-1 : 3626,3374,3288,29
60,1785,1436,1331 NMR (CDCl ₃ ) δ: 1.08 (3H, t, J = 7.2 Hz,
CH ₃ ), 1.44 (18H, s, 2 × ^t Bu), 2.90-3.
22 (2H, m, CH ₂ ), 3.07 (2H, d, J = 7.6Hz,
CH ₂ ), 3.94 (1 H, dt, J = 5.0, 7.6 Hz, C
H), 4.25 (1H, broadt, J = 6.0 Hz, NH), 5.
38 (1H, s, OH), 5.72 (1H, d, J = 5.0Hz, C
H), 7.12 (2H, s, 2 × aromatic-H) Elemental analysis (C ₂₀ H ₃₁ NO ₅ S) Calculated C, 60.43; H, 7.86; N, 3.52; S ,
8.07 found C, 60.32; H, 7.84; N, 3.55; S,
7.85

(6) (E) -4- (3,5-di-tert-butyl)
Tyl-4-hydroxyphenyl) -3- (N-ethylsul
Famoyl) -3-butenoic acid (19)

Embedded image 5- (3,5-di-tert-4-hydroxyphenyl) -4
-(N-ethylsulfamoyl) -γ-butyrolactone
A solution of ( 18 ) (1.516 g, 3.81 mmol) in benzene (5
DBU (1.14 mmol, 7.62 mmol) was added to the mixture, and the mixture was stirred under the same conditions for 30 minutes. 1N-HCl (60m
l) and extract with ethyl acetate (70 ml). The organic layer was separated, washed with water (60 ml) and saturated saline (60 ml), and dried over anhydrous sodium sulfate. When the solvent is distilled off under reduced pressure, 1
9 was obtained as a colorless solid. Yield 1.52 g (quant) mp. 169-172 ° C IR (KBr) cm ^-1 : 3604,3267,2958,171
9,1631,1596,1430,1326,1158 NMR (CD ₃ OD) δ: 1.15 (3H, t, J = 7.4 Hz,
CH ₃ ), 1.43 (18H, s, 2 × ^t Bu), 2.99 (2H,
q, J = 7.4 Hz, CH ₂ ), 3.63 (2 H, s, CH ₂ ), 7.
29 (2H, s, 2 × aromatic-H), 7.58 (1H, s, C
H) Elemental analysis (C ₂₀ H ₃₁ NO ₅ S) Calculated C, 60.43; H, 7.86; N, 3.52; S,
8.07 found C, 60.36; H, 7.95; N, 3.54; S,
7.87

(7) (E) -5- (3,5-di-tert-
Butyl-4-hydroxy) benzylidene-2-ethyl
-1,2-isothiazolidine-3-one-1,1-dio
Quicide (8 Ig)

Embedded image (E) -N-ethylaminosulfonyl-4- (3,5-di-tert-butyl-4-hydroxy) phenyl-3-butenoic acid 19 (1.52 gr, 3.81 mmol) and triethylamine (0.737 ml) , 1.5 equivalents) in methylene chloride solution (60 ml), ethyl chloride (0.437 ml, 1.2 equivalents) was added dropwise while stirring and cooling with ice water.
Stir for 0 minutes. Water (60 ml) was added to the reaction solution, extracted with methylene chloride (50 ml), and the organic layer was washed with saturated saline (70 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude crystals were washed with ether to give the target compound as colorless columnar crystals. yield
1.30 gr (89.9%). 8Ig: mp 188-190 ° C IR (KBr) cm ^-1 : 3559, 2960, 171
5,1641,1598,1434,1317,115
9 NMR (CDCl ₃ ) δ: 1.38 (3H, t, CH ₃ ),
1.46 (18H, s, 2 × Bu t), 3.74 (2H,
q, J = 7.2 Hz, CH ₂ ), 3.80 (2H, d, J =
2.4 Hz, CH ₂ ), 5.64 (1H, s, OH), 7.
23 (2H, s, Ar-H), 7.45 (1H, t, J =
2.4 Hz, CH) Elemental analysis (C ₂₀ H ₂₉ NO ₄ S) Calculated: C, 63.30; H, 7.70; N, 3.6
9; S, 8.45 Found: C, 63.07; H, 7.71; N, 3.7
2; S, 8.30

Example 37 (E) -5- (3,5-Di-tert-butyl-4-hydro
Xy) benzylidene-2-ethyl-3-hydroxy-
1,2-isothiazolidine-1,1-dioxide 8I
h

Embedded image In a methylene chloride solution (30 ml) of compound 8Ig (870 mg, 2.29 mmol), diisobutylaluminum hydride (DIBA
L) A solution (1.0 M hexane; 4.22 ml) was added dropwise.
After about 5 minutes, a saturated aqueous ammonium chloride solution (3
0 ml), and the resulting slurry was filtered through celite.
A saturated aqueous ammonium chloride solution (70 ml) is added to the filtrate, and the mixture is extracted with ethyl acetate (100 ml). The organic layer was washed with saturated saline (100 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
Recrystallization from a hexane: ether mixture gave the target compound as colorless columnar crystals. Yield 762 mg (87.2
%). 8Ih: mp 138-141 ° C IR (KBr) cm ⁻¹ : 3610, 3427, 296
8, 1653, 1595, 1432, 1261, 121
4,1147 NMR (d ₆ -acetone) δ: 1.27 (3H, t, J = 7.
0 Hz, CH ₃ ), 1.48 (18 H, s, 2 × B
u ^t ), 3.01 to 3.12 (1H, m, CH), 3.27
(2H, q, J = 7.0 Hz, CH ₂ ), 3.57 (1H,
m, CH), 5.21 to 5.24 (1H, m, CH (O
H)), 5.35 (1H, broad, OH), 7.18 (1
H, t, J = 2.4 Hz, CH), 7.37 (2H, s, A
r-H) Elemental analysis _{(C 20 H 31 NO 4 S} ) Calculated: C, 62.96; H, 8.19 ; N, 3.6
7; S, 8.40 Found: C, 63.05; H, 8.26; N, 3.6
7; S, 8.33

Example 38 (E) -5- (3,5-Di-tert-butyl-4-hydro
Xy) benzylidene-2-ethyl-dihydro-5H-
1,2-isothiazole-1,1-dioxide (8I
i)

Embedded image T of compound 8Ih (342 mg, 0.896 mmol)
2N hydrochloric acid (1 drop) was added to HF solution (30 ml),
Stir at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate (3
5 ml), extract with ethyl acetate (30 ml), wash the organic layer with saturated saline (35 ml), and dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude crystals were recrystallized from a mixed solution of n-hexane and ether to give the target compound as orange columnar crystals. Yield 296 mg (90.8
%). 8Ii: mp 135-137 ° C IR (KBr) cm ^-1 : 3608,3472,296
1,1593,1560,1435,1392,130
0,1212,1153 NMR (CDCl ₃ ) δ: 1.40 (3H, t, J = 7.2)
_{Hz, CH 3), 1.43 (} 18H, s, 2 × Bu t),
3.52 (2H, q, J = 7.2Hz, CH 2), 5.50
(1H, s, OH), 6.22 (1H, dd, J = 0.8,
6.2 Hz, CH), 6.54 (1H, dd, J = 1.8,
6.2 Hz, CH), 6.84 (1H, broad, CH), 7.
30 (2H, s, Ar- H) Elemental analysis _{(C 20 H 29 NO 3 S} ) Calcd: C, 66.08; H, 8.04 ; N, 3.8
5; S, 8.82 Found: C, 66.53; H, 8.08; N, 3.8
2; S, 8.68

[0101]

Embedded image Reference Example _{^{1 (R 3 = CH 2 CH}} 2 CH 3) N-n- propyl-1,2-isothiazolidine-1,1
Dioxide (4e) in γ-sultone (12.2 gr, 0.1 mol) under ice-cooling and stirring.
-Propylamine (5.9 gr, 0.1 mol) was added. The contents solidified as the reaction progressed. Phosphorus oxychloride (10 ml) was added to the solid product, and the mixture was heated under reflux for 2 hours. The residual phosphorus oxychloride was distilled off under reduced pressure. Dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound 4e as a colorless oil. This product was consistent with the preparation obtained in Production Example 5. Yield 15.2gr (93%)

Reference Example 2 (R ³ ＣＨCH ₂ CH (CH ₃ ) ₂ ) N-isobutyl-1,2-isothiazolidine-1,1-di
Oxide (4c) γ-sultone (12.2 gr,
0.1 mol), isobutylamine (7.3 gr, 0.1 mol) and phosphorus oxychloride (10 ml) were reacted to obtain the desired compound 4c. This product was identical to the preparation obtained in Production Example 3. Yield 15.9gr (90%)

The usefulness of the compound I of the present invention prepared in the above example as an anti-inflammatory agent was tested in vivo and in vitro. In addition, among the control compounds in the following test examples,
E-5110 is N-methoxy-3- (3,5-di-t-
Butyl-4-hydroxybenzylidene) -2-pyrrolidone (described in JP-A-61-257967). Test Example 1 PGE ₂ production inhibitory action in rat synovial cells LEW / Crj male rats (body weight 300-350 g)
Were collected and subcultured under certain conditions to the number of cells required for the experiment. 4 × 10 ^{3 of} cultured synovial cells
/ 160μl / well and put in 96-well plate,
The cells were cultured in a CO ₂ incubator for 72 hours. afterwards,
20 μl of various concentrations of test drug and 20 μl of human IL-1β
(30 U / ml final concentration) were added simultaneously, and the mixture was reacted in a CO ₂ incubator for 15 hours, and the supernatant was stored at −80 ° C. until PGE ₂ measurement. Measurement of PGE ₂ after melting the stored samples was performed by RIA using ¹²⁵ I-PGE _2.
Table 1 shows the results.

Test Example 2 LTB in rat peritoneal cells
₄ Production inhibitory action 0.1% bovine serum albumin (BSA) and 2% intraperitoneally in Jci-SD male rats (body weight 300-350 g).
After injecting 10 ml of Hanks' solution containing 5 U / ml heparin, ascites was collected and centrifuged at 1500 rpm for 5 minutes at 4 ° C. The cell fraction (precipitate) was added to Hanks' containing 0.1% BSA.
The suspension was adjusted to 1 × 10 ⁶ cells / ml. 800 μl (8 × 10 ⁵ cells) of the adjusted peritoneal cells were transferred to a polypropylene tube and incubated at 37 ° C. for 10 minutes. Then, 100 μl of various concentrations of the test drug were added, and the mixture was further incubated for 10 minutes. Then, 100 µl of Ca-ionophore A23187 (final concentration: 1 µM) was added to add 15 µl.
After reacting for 1 minute, the reaction was stopped by cooling with ice,
After centrifugation at 0 rpm x 5 minutes, the supernatant was collected and -80 until measurement.
Stored at ° C. Measurements of LTB ₄ after melting the stored samples, ³
Using H-LTB _4, it was performed in RIA. Table 1 shows the results.

Test Example 3 LPS in THP-1 cells
IL-1 production inhibitory action THP-1 cells under stimulation was dispersed in RPMI1640, 1 Anaate in 24-well plates, cell suspension 800 [mu] l (5x10 ⁶ cells / ml), various concentrations of test drug 100 [mu] l, LPS10
The reaction was started by adding 0 μl (final concentration: 10 μg / ml). After standing at 37 ° C. for 24 hours, the supernatant was recovered and collected for 30 hours.
After centrifugation at 00 rpm × 10 minutes, the supernatant was collected. IL-1
Was measured using ¹²⁵ I-IL-1β and the RI
A. Table 1 shows the results.

[0106]

[Table 1]

Test Example 4 Rat Carrageenin Paw Edema Inhibitory Activity The method of Winter et al. (Winter, CA. Proc. So
c. Exp. Biol. Med., Vol. 111, p. 54, 1962)
Was improved. That is, LEW / Crj male rats (6 weeks old, body weight 140-170 g) were cultured for 24 days from the day before the experiment.
They were fasted for a period of time and used as 7-8 animals per group. One hour after oral administration of the drug, 1% λ-carrageenin (PICININ-A, Z
Edema was induced by subcutaneously injecting 0.1 ml of the ushikagaku) solution into the right hind footpad. The paw volume of the right hind limb was determined with a water displacement volume meter before carrageenan injection and every hour after the injection until 5 hours later. The inhibition rate of the drug administration group relative to the vehicle administration group was calculated, and the efficacy was determined by Dunnett-t test.
The anti-edema effect of the drug was determined by the regression analysis based on the inhibition rate at 3 or 4 hours after carrageenan administration, using the ED ₅₀ (mg / K
g). Table 2 shows the results.

Test Example 5 Rat Gastric Mucosal Injury Inhibiting Activity LEW / Crj male rats (6 weeks old, body weight 140-1)
60 g) was used as 6 animals per group. The drug was orally administered to rats fasted for 24 hours from the day before the experiment, and 6 hours later, the animals were exsanguinated and killed under ether anesthesia. The stomach was excised, sealed with about 6 ml of physiological saline, and immersed in 1% formalin solution for about 15 minutes. The stomach was incised along the great bay, and the damage state of the gastric mucosa was observed under a microscope, and the number of gastric lesions and the length of hemorrhagic spots were measured. For the degree of disability, the cumulative value of the length of the bleeding spot of each administration group was shown as Lesion Index (mm). Further, the strength of the action of the drug was displayed by calculating UD ₅₀ (mg / Kg) by the probit method from the number of onsets corresponding to the dose of each drug. Table 2 shows the results.

[0109]

[Table 2]

Formulation Example 1 1) Granules Compound 8a 20 mg Lactose 250 mg Corn Starch 115 mg Hydroxypropylcellulose 115 mg The above-mentioned raw materials are converted into granules by a conventional wet method.

[Effect of the Invention] It has an activity to suppress the production of PGE ₂ , LTβ ₄ and IL-1, etc., and is expected to have an anti-inflammatory effect.

Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication A61K 31/44 A61K 31/44 31/535 31/535 31/54 31/54 C07D 275/02 C07D 275/02 279/02 279/02 291/04 291/04 291/06 291/06 327/04 327/04 327/06 327/06 333/48 333/48 335/02 335/02 409/04 333 409/04 333 335 335 417/06 213 417/06 213

Claims (5)

(57) [Claims] 1. Formula I: ## STR1 ## [In the formula, A is -CH ₂ - or -CH ₂ CH ₂ -; B is
Or represents a bond or _{-CH 2 -, - CHOH -,} - CO
-, -O-, or A and B together form -CH = C
H- may be formed; D is> N- or>
R ¹ and R ² are each independently hydrogen, lower alkyl or lower alkoxy; R ³ is hydrogen, lower alkyl, cycloalkyl, lower alkoxy; arylalkyloxy, heteroarylalkyloxy, lower alkylcarbonyl, Arylcarbonyl, substituted or unsubstituted carbamoyl, or a formula: — (CH ₂ ) _n —R ⁴ , wherein R ⁴ is hydrogen, hydroxy, substituted or unsubstituted amino, aryl, heteroaryl, hydroxycarbonyl or lower alkyloxy Carbonyl; n is 0-3
Which represents an integer of the following). 2. The compound of claim 1 wherein R ¹ and R ² are t-butyl. 3. A is —CH ₂ —, B is —CH ₂ —, and D is>
3. The compound according to claim 1, which is N-. 4. The compound according to claim 1, wherein R ³ is lower alkyl or cycloalkyl. 5. An anti-inflammatory agent comprising the compound of claim 1 as an active ingredient.